Janus Kinase Inhibitor (Baricitinib) for Aicardi Goutières Syndrome
Phase: PHASE2
Conditions: Aicardi Goutieres Syndrome
Sponsor: Adeline Vanderver, MD

 
Template version: May 28, 2014 
  
Title: 
Janus Kinase Inhibitor (Baricitinib) for Aicardi Goutières 
Syndrome 
Short Title 
JAK inhibitor treatment in AGS 
Drug or Device 
Name(s): 
Baricitinib  
FDA IND 
140510 
Regulatory Sponsor: 
Adeline Vanderver, MD 
eIRB Number 
18-015414 
Protocol Date: 
11 April 2019 
Amendment 1:  23 Jun 2020 (Full Amd.) 
Amendment 9: 17 Sep 2020 (Full Amd.) 
Amendment 12: 13 Jul 2021 (Full Amd.) 
Amendment 19: 29 Jul 2021 (Full Amd.) 
Amendment 22: 12 Jan 2022 (Full Amd.) 
Amendment 24: 18 Mar 2022 (Full Amd.) 
Amendment 28: 19 August 2022 (Full Amd.) 
Amendment 32: 02 May 2023 (Full Amd.) 
Amendment 36: 30 Oct 2023 (Full Amd.) 
Amendment 44: 05 Feb 2025 (Full Amd.) 
Please note that the above list does not include ‘Staff Change’ amendments. 
 
IND holder 
Adeline Vanderver, MD 
Program Director of the Leukodystrophy Center of Excellence 
Children’s Hospital of Philadelphia 
Associate Professor of Neurology 
3615 Civic Center Blvd. 
Abramson Research Center 516H 
Philadelphia, PA 19104 
Phone: 215-590-1719 
Fax:215-590-1234 
Email: vandervera@chop.edu  
 
Study Principal Investigator  
Adeline Vanderver, MD 
Program Director of the Leukodystrophy Center of Excellence 
Children’s Hospital of Philadelphia 
Associate Professor of Neurology 
3615 Civic Center Blvd. 
Abramson Research Center 516H 

 
 
 
 
 
 
 
 
ii
Philadelphia, PA 19104 
Phone: 215-590-1719 
Fax:215-590-1234 
Email: vandervera@chop.edu  
 
Study Biostatistician:  
Justine Shults, PhD 
Children’s Hospital of Philadelphia 
Professor of Biostatistics 
4471 Roberts Center for Pediatric Research 
624R Schuylkill Ave 
Philadelphia, PA 19146 
Phone: 215-518-8628 
Fax: 215-590-1234 
Email: shultsj@chop.edu 
 
Medical Monitor:   
Nicole Jaffe, MD 
Clinical Assistant Professor of Pediatrics 
Complex Care Pediatrics 
Children’s Hospital of Philadelphia 
34th and Civic Center Blvd 
Philadelphia, PA 19104 
Email: jaffen@chop.edu  
 
Co-investigators: 
 
Laura Adang, MD PhD 
Instructor, Department of Neurology 
Children’s Hospital of Philadelphia 
34th and Civic Center Blvd 
Philadelphia, PA 19104 
Email: adangl@chop.edu 
 
Amy Waldman, MD 
Assistant Professor, Department of Neurology 
Children’s Hospital of Philadelphia 
34th and Civic Center Blvd 
Philadelphia, PA 19104 
Email: waldman@chop.edu 
 
Please refer to FDA form 1572 and the eIRB application for an exhaustive 
list of co-investigators and other study team members. 
 

 
 
  
 
 
 
 
 
 
iii
TABLE OF CONTENTS 
Table of Contents ...................................................................................................... iii 
Abbreviations and Definitions of Terms ................................................................ vi 
Abstract ...................................................................................................................... ix 
Protocol Synopsis ...................................................................................................... x 
1 
BACKGROUND INFORMATION AND RATIONALE ................................................................... 1 
1.1 
INTRODUCTION ................................................................................................................................. 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ....................................... 3 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ...................................................................... 4 
1.3.1 
Non-Clinical Studies ............................................................................................................... 4 
1.3.2 
Clinical Studies....................................................................................................................... 5 
1.4 
SELECTION OF DRUGS AND DOSAGES ............................................................................................... 9 
1.5 
RELEVANT LITERATURE AND DATA .................................................................................................. 10 
1.6 
COMPLIANCE STATEMENT ............................................................................................................... 14 
2 
STUDY OBJECTIVES ................................................................................................................. 14 
2.1 
PRIMARY OBJECTIVE (OR AIM) ........................................................................................................ 14 
2.2 
SECONDARY OBJECTIVES (OR AIM) ................................................................................................. 14 
3 
INVESTIGATIONAL PLAN ......................................................................................................... 15 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ............................................................................................. 15 
3.1.1 
Transfer of patients from the Compassionate Use Treatment Protocol I4V-MC-JAGA ...... 15 
3.1.2 
Additional subjects ............................................................................................................... 15 
3.1.3 
Allocation to Treatment Groups and Blinding ...................................................................... 16 
3.2 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................. 16 
3.2.1 
Duration of Study Participation ............................................................................................ 16 
3.2.2 
Total Number of Study Sites/Total Number of Subjects Projected ..................................... 16 
3.3 
STUDY POPULATION ....................................................................................................................... 16 
3.3.1 
Patients from the Compassionate Use Treatment Protocol 14V-MC-JAGA ....................... 16 
3.3.2 
Inclusion Criteria .................................................................................................................. 16 
3.3.3 
Exclusion Criteria ................................................................................................................. 17 
4 
STUDY PROCEDURES .............................................................................................................. 21 
4.1 
UNFORESEEABLE EMERGENCY EVENTS ........................................................................................... 21 
4.2 
PRE-SCREENING PERIOD ................................................................................................................ 21 
4.3 
SCREENING VISIT ........................................................................................................................... 21 
4.4 
STUDY TREATMENT PHASE ............................................................................................................. 22 
4.4.1 
Enrollment ............................................................................................................................ 22 
4.4.2 
Initial Treatment and Dose Escalation ................................................................................. 23 
4.5 
CONTINUING TREATMENT ................................................................................................................ 24 
4.5.1 
Continuing treatment for patients transferred from the JAGA Compassionate Use study .. 24 
4.6 
IMMUNOSUPPRESSION MONITORING DURING CONTINUING TREATMENT .............................................. 25 
4.7 
CONCOMITANT MEDICATION............................................................................................................ 25 
4.8 
DOSING CHANGES .......................................................................................................................... 26 
4.9 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................. 26 
4.9.1 
Early Termination Study Visit ............................................................................................... 26 
5 
STUDY EVALUATIONS AND MEASUREMENTS ..................................................................... 27 
5.1 
SCREENING AND MONITORING EVALUATIONS: PERFORMED AS PART OF CLINICAL CARE ................... 27 
5.1.1 
Physical Examination ........................................................................................................... 27 
5.1.2 
Vital Signs ............................................................................................................................ 27 
5.1.3 
Cardiac monitoring ............................................................................................................... 27 
5.1.4 
Electrocardiograms .............................................................................................................. 27 

 
 
  
 
 
 
 
 
 
iv 
5.1.5 
Chest X-ray and tuberculosis screening .............................................................................. 28 
5.1.6 
Laboratory Evaluations ........................................................................................................ 28 
5.1.7 
Medical Record Review ....................................................................................................... 28 
5.1.8 
Pregnancy Testing ............................................................................................................... 28 
5.2 
SCREENING AND MONITORING EVALUATIONS: PERFORMED AS A PART OF RESEARCH ....................... 28 
5.2.1 
Physical Examination ........................................................................................................... 28 
5.2.2 
Vital Signs ............................................................................................................................ 29 
5.2.3 
Symptom Diaries .................................................................................................................. 29 
5.2.4 
AGS Scale............................................................................................................................ 29 
5.2.5 
GMFM-88 ............................................................................................................................. 29 
5.2.6 
AGS Development ............................................................................................................... 30 
5.2.7 
Skin Inflammation ................................................................................................................ 30 
5.2.8 
Cardiac monitoring ............................................................................................................... 31 
5.2.9 
Electrocardiograms .............................................................................................................. 31 
5.2.10 
Chest X-ray and tuberculosis screening .............................................................................. 31 
5.2.11 
Bone growth monitoring ....................................................................................................... 31 
5.2.12 
Laboratory Evaluations ........................................................................................................ 32 
5.2.13 
Safety Evaluation ................................................................................................................. 33 
5.2.14 
Administration of Study Drug ............................................................................................... 33 
5.2.15 
Medical Record Review ....................................................................................................... 33 
5.2.16 
Pregnancy Testing ............................................................................................................... 33 
5.2.17 
Pharmacokinetic Evaluation ................................................................................................ 33 
5.2.18 
IFN Signaling Gene Score ................................................................................................... 34 
5.2.19 
Leftover Samples for Future Research ................................................................................ 34 
6 
STATISTICAL CONSIDERATIONS ............................................................................................ 35 
6.1 
PRIMARY ENDPOINT ....................................................................................................................... 35 
6.2 
SECONDARY ENDPOINTS ................................................................................................................ 35 
6.3 
STATISTICAL METHODS .................................................................................................................. 35 
6.3.1 
Baseline Data and Descriptive Analysis .............................................................................. 35 
6.3.2 
Primary Outcome Analysis................................................................................................... 36 
6.3.3 
Secondary Outcome Analysis .............................................................................................. 36 
6.3.4 
Pharmacokinetic Analysis .................................................................................................... 39 
6.3.5 
Safety Analysis..................................................................................................................... 39 
6.4 
SAMPLE SIZE AND POWER .............................................................................................................. 39 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) ..................... 41 
7.1 
DESCRIPTION ................................................................................................................................. 41 
7.1.1 
Packaging ............................................................................................................................ 41 
7.1.2 
Labeling ................................................................................................................................ 41 
7.1.3 
Dosing .................................................................................................................................. 41 
7.1.4 
Treatment Compliance and Adherence ............................................................................... 41 
7.1.5 
Drug Accountability .............................................................................................................. 41 
8 
SAFETY MANAGEMENT............................................................................................................ 42 
8.1 
CLINICAL ADVERSE EVENTS ............................................................................................................ 42 
8.2 
ADVERSE EVENT REPORTING ......................................................................................................... 42 
8.3 
DEFINITION OF AN ADVERSE EVENT ................................................................................................ 42 
8.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) .......................................................................... 42 
8.4.1 
Expected and Unexpected Adverse Events ........................................................................ 43 
8.4.2 
Relationship of SAE to study drug or other intervention ...................................................... 44 
8.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ....................................... 45 
8.5.1 
Reporting of Serious Adverse Events .................................................................................. 45 
8.5.2 
Suspected Unexpected Serious Adverse Reactions ........................................................... 46 
8.5.3 
Follow-up report ................................................................................................................... 46 
8.6 
NOTIFICATIONS OF SAES/IND SAFETY REPORTS TO THE FDA ......................................................... 46 

 
 
  
 
 
 
 
 
 
v
8.7 
STUDY STOPPING RULES ................................................................................................................ 46 
8.8 
SAFETY MANAGEMENT AND MONITORING GUIDANCE ....................................................................... 47 
9 
STUDY ADMINISTRATION......................................................................................................... 48 
9.1 
TREATMENT ASSIGNMENT METHODS ............................................................................................... 48 
9.1.1 
Randomization ..................................................................................................................... 48 
9.1.2 
Blinding ................................................................................................................................ 48 
9.1.3 
Unblinding ............................................................................................................................ 48 
9.2 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 48 
9.2.1 
REDCap for Study Data Management................................................................................. 48 
9.2.2 
Additional Study Data Management .................................................................................... 48 
9.3 
CONFIDENTIALITY ........................................................................................................................... 51 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS ................................................................................. 51 
9.4.1 
Data and Safety Monitoring Plan ......................................................................................... 51 
9.4.2 
Risk Assessment ................................................................................................................. 52 
9.5 
BENEFITS ....................................................................................................................................... 58 
9.5.1 
Potential Benefits of Trial Participation ................................................................................ 58 
9.5.2 
Risk-Benefit Assessment ..................................................................................................... 58 
9.6 
RECRUITMENT STRATEGY ............................................................................................................... 58 
9.7 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................. 59 
9.7.1 
Waiver of Consent and HIPAA Authorization ...................................................................... 61 
9.7.2 
Waiver of Assent .................................................................................................................. 62 
9.8 
COMPLIANCE .................................................................................................................................. 62 
9.8.1 
Regulatory Compliance........................................................................................................ 62 
9.8.2 
Investigator Assurances....................................................................................................... 62 
9.8.3 
Records Retention and Requirements................................................................................. 62 
9.8.4 
Financial Disclosure ............................................................................................................. 62 
9.8.5 
Regulatory Files ................................................................................................................... 63 
9.8.6 
Monitoring ............................................................................................................................ 63 
9.8.7 
Modification of the Protocol.................................................................................................. 63 
9.8.8 
Protocol Violations ............................................................................................................... 63 
9.9 
PAYMENT TO SUBJECTS/FAMILIES ................................................................................................... 64 
10 
PUBLICATION..................................................................................................................... 64 
Appendix.................................................................................................................... 12 
  

 
 
  
 
 
 
 
 
 
vi 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Definition 
Adverse event (AE) Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) product. 
AGS 
Aicardi Goutières Syndrome 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
Assent 
Agreement from a child or other individual who is not legally capable of 
providing consent, but who can understand the circumstances and risks 
involved in participating in a study (required by some institutional review 
boards [IRBs]). 
AST 
Aspartate aminotransferase 
Audit 
A systematic and independent examination of the trial-related activities 
and documents to determine whether the evaluated trial-related activities 
were conducted, and the data were recorded, analyzed, and accurately 
reported according to the protocol, applicable standard operating 
procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s). 
Compliance 
Adherence to all the trial-related requirements, good clinical practice 
(GCP) requirements, and the applicable regulatory requirements. 
CSF 
Cerebrospinal fluid 
CXR 
Chest X-ray 
ECG 
Electrocardiogram 
Electronic case 
report form (eCRF) 
Sometimes referred to as clinical report form. A printed or electronic form 
for recording study participants’ data during a clinical study, as required 
by the protocol. 
Effectiveness 
Effectiveness is the measure of the produced effect of an intervention 
when carried out in a clinical environment. 
eGFR 
Estimated glomerular filtration rate 
End of the study 
End of study (trial) is the date of the last visit or last scheduled procedure 
shown in the Study Schedule for the last active patient in the study. 

 
 
  
 
 
 
 
 
 
vii
Enrollment 
The act of assigning a patient to a treatment. Patients who are enrolled 
in the trial are those who have been assigned to a treatment. 
Enter 
The act of obtaining informed consent for participation in a clinical trial 
from patients deemed eligible or potentially eligible to participate in the 
clinical trial. Patients entered into a trial are those who sign the informed 
consent form directly or through their legally acceptable representatives. 
GCP 
Good clinical practice 
GEE 
Generalized estimating equation 
GMFM-88 
Gross Motor Function Measure-88 
HBV 
Hepatitis B virus 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
IFN 
Interferon 
IL 
Interleukin 
Institutional review 
board/ethical review 
board (IRB/ERB) 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that 
the safety, welfare, and human rights of the patients participating in a 
clinical study are protected. 
IP-10/CXCL10 
Interferon inducible protein 10/ C-X-C motif chemokine 10 
ISG 
Interferon stimulating genes 
IV 
Intravenous 
IVIg 
Intravenous immune globulin 
JAK 
Janus kinase 
Legal representative An individual, judicial, or other body authorized under applicable law to 
consent on behalf of a prospective patient to the patient’s participation in 
the clinical study. 
MDBP 
Myelin Disorders Biorepository Project 
Patient 
A study participant who has the disease or condition for which the 
investigational product is targeted. 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic 
PPD 
Purified protein derivative 
QD 
Once daily 
QLS 
Quasi-Least Squares 
RA 
Rheumatoid arthritis 
SAE 
Serious adverse event 

 
 
  
 
 
 
 
 
 
viii
 
Screen 
The act of determining if an individual meets minimum requirements to 
become part of a pool of potential candidates for participation in a clinical 
study. In this study, screening involves diagnostic procedures and/or 
tests (for example, x-rays, blood draws). For this type of screening, 
informed consent for these screening procedures and/or tests shall be 
obtained; this consent may be separate from obtaining consent for the 
study. 
SLE 
Systemic lupus erythematosus 
STAT 
Signal transducers and activators of transcription 
STING 
Stimulator of interferon genes 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
Treatment-emergent 
adverse event 
(TEAE) 
Any untoward medical occurrence that either occurs or worsens at any 
time after treatment baseline and that does not necessarily have to have 
a causal relationship with this treatment. 
ULN 
Upper limit of normal 
WBC 
White blood cell 

 
 
  
 
 
 
 
 
 
ix 
ABSTRACT 
Context: (Background) 
Aicardi Goutières Syndrome (AGS) is a multisystem, heritable disorder of innate 
immunity resulting in excessive interferon production. Interferon production causes 
injury to the brain, as well as 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. 
Objectives: (Primary and important secondary objectives) 
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 from baseline to 52 weeks of treatment. 
The secondary objectives include assessments of safety parameters, of therapeutic 
endpoints including an AGS symptom diary score; a surrogate biomarker, the interferon 
signaling gene score; and of functional neurologic measures (including GMFM-88 and 
longitudinal AGS scale measurements [in addition to and including baseline and 52 
weeks]). 
Study Design:  
Open-label phase 2 clinical study. 
Setting/Participants: 
The setting: outpatient  
The number of sites: single center 
The number and description of participants including key eligibility criteria: eligible 
patients will have AGS with symptoms of neurologic disability, laboratory evidence of 
AGS related disease, or skin involvement, and no exclusion criteria making the 
administration of baricitinib less safe. 
Clinical care and research procedures will be used to generate data about the use of 
baricitinib in patients affected by AGS, which may potentially help to improve treatment 
outcomes for subjects within this patient population. 
Study Interventions and Measures:  
The research procedures include physical examination, vital signs, symptom diaries (for 
at least two years from treatment initiation), medical record review, functional neurologic 
measures such as the GMFM-88 assessment or the AGS scale, assessment of skin 
inflammation, laboratory evaluations and phlebotomy including PK testing and leftover 
samples for future research, interferon signaling scores, pregnancy testing, and 
administration of baricitinib. Throughout the protocol, note that the term “study 
interventions” includes clinical and research procedures used to generate study data. 
Main study outcome measures include the AGS scale, symptom diaries, safety 
monitoring, functional assessments of neurologic function (ie GMFM-88), and interferon 
signaling gene scores. 

 
page x 
  
 
 
 
PROTOCOL SYNOPSIS 
Name of Investigational Product: 
Baricitinib, orally or G-tube administered 
Title of Study:  
Janus Kinase Inhibitor (Baricitinib) for Aicardi 
Goutières Syndrome 
Length of Study:  
Each patient may be treated up to 288 weeks. 
Number of Planned 
Patients/Subjects: 
Entered: up to 55  
Enrolled: up to 55 
Completed:  up to 55 
Study Objective: 
To assess safety and efficacy of baricitinib in 
individuals affected by Aicardi Goutières Syndrome 
Study Population 
and Main Eligibility/ Exclusion 
Criteria: 
Individuals with Aicardi Goutières Syndrome with 
evidence of AGS related neurologic or systemic 
disease and without systemic medical problems 
placing them at higher risk for treatment with 
baricitinib.  
Primary Outcome Measures: 
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 from baseline to 52 weeks.  
Secondary Outcome Measures:  
Secondary objectives will include assessments of 
safety parameters, improvement of interferon 
signaling scores, improvement of AGS scale 
(longitudinal) and GMFM-88, and improvement of a 
daily disease severity scale, for the duration of the 
treatment period. 

 
page xi 
  
 
 
 
Study Design: 
Open- label, phase 2 clinical study. 
Statistical Considerations (sample 
size and analysis plan): 
The change over time in AGS scale will be 
compared pre and post treatment with a GEE 
analysis that accounts for age at treatment 
initiation. Sensitivity analyses will also be 
performed, to evaluate the efficacy of treatment 
across several statistical approaches with varying 
assumptions. 
Sample size considerations were based on 
preliminary data. In preliminary data, the average 
of within subject changes (post-treatment average 
minus pre-treatment average) was 0.80 with a 
standard deviation of changes of 1.04. This 
corresponds to an effect-size of 0.80/1.04 = 0.77. 
From PASS 16, a sample size of 30 data pairs 
achieves 98.3% power to reject the null hypothesis 
of zero effect size when the population effect size 
is 0.77 and the significance level (alpha) is 0.050 
using a two-sided paired t-test. Should the effect-
size be smaller than we observed in our 
preliminary data, we will have 80% power to detect 
an effect size of 0.53, which corresponds to an 
average of within subject changes of 0.55, if the 
SD of changes is 1.04. 
Funding Sponsors (federal, state, 
foundation and industry support): 
Drug and grant support provided as a donation by 
Eli-Lilly  
Secondary funder: Pennsylvania Department of 
Health 

 
 
 
 
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
The purpose of this immediate and delayed phase study protocol is to establish safety 
and efficacy of baricitinib in individuals with Aicardi Goutières Syndrome (AGS), a 
heritable disorder of excessive interferon (IFN) production, occurring in fewer than 1/7000 
live births1, that affects brain, skin, bone marrow and visceral organs. This rare condition 
is well positioned for new therapeutic innovations due to growing interest in targeting 
interferon pathways also implicated in more common disorders such as lupus and 
rheumatoid arthritis. In addition, AGS is increasingly well characterized, with an 
established course of disease2, improved early recognition through laboratory criteria3,4 , 
MRI2,5, and well characterized genotyping6-9. Genetic abnormalities in viral sensing genes 
(TREX1, 
RNASEH2A, 
RNASEH2B, 
RNASEH2C, SAMHD1, ADAR1, IFIH16-9) 
trigger an endogenous IFN response 
resulting in extensive end organ damage. 
(Figure 1). IFNs, increased in blood and 
cerebrospinal fluid in AGS10,11, are thought 
to be directly responsible for disease 
pathology. Transgenic animal models of 
IFN 
overexpression 
in 
astrocytes 
demonstrate 
a 
thrombotic 
microangiopathy12, similar to pathology 
seen in AGS brain and skin lesions13-15. 
There is evidence of vascular injury in vitro 
in vascular endothelial cells exposed to 
IFN14 and in humans treated with 
recombinant IFN16, suggesting tissue 
specific injury. New data suggests that 
treatment with IFN blockade using 
Janus Kinase (JAK) inhibitors may be beneficial in interferon mediated disorders. Since 
opening our expanded access use program for baricitinib, a JAK inhibitor, in 
February 2017, we have enrolled more than twenty individuals. Preliminary data17,18 
suggests improvement in patient reported scores and expression of IFN signaling genes, 
however, more comprehensive and longer-term study is needed to assess clinical benefit 
of this therapeutic approach. 
Aicardi-Goutières Syndrome (AGS) is an inflammatory disease particularly affecting 
the brain (causing severe damage to the white matter as well as the deposition of 
calcium in both white and grey matter) and the skin (resulting in so- called chilblain 
lesions affecting the toes, fingers and ears in particular), but also demonstrating 
systemic features (for example, glaucoma, cardiomyopathy, pulmonary hypertension, 
myopathy, neuropathy, endocrinologic problems) in many patients. All available 
literature sources suggest that the prevalence of AGS is well below 5 in 10,000 persons. 
AGS is a genetically heterogeneous Mendelian disease, occurring due to mutations in 
any of the genes encoding the DNA exonuclease TREX1 (TREX1), the three non- allelic 
components of the RNase H2 endonuclease complex (RNASEH2A, RNASEH2B, and 
Figure 1. Multisystemic effects of AGS-related 
interferon 
include 
primary 
neurologic 
involvement 
including 
leukodystrophy 
with 
a 
calcifying thrombotic microangiopathy, microcephaly, 
seizures and severe developmental delay. 
Nearly 100%
Chilblains ~ 30%
Glaucoma 6%
Hypothyroidism 
4%
Cardiomyopathy 3%
Autoimmune hepatitis, NA%
Hematologic 
abnormalities, 
NA%
Joint 
contractures/ 
inflammation, 
NA%
Lupus like 
nephropathy, 
NA%
Inflammatory 
bowel disease 
<4%

 
 
 
 
 
 
 
2
RNASEH2C), the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 
(SAMHD1), the double-stranded RNA editing enzyme ADAR (ADAR), and the double-
stranded RNA cytosolic sensor IFIH1/MDA5 (IFIH1). 
The proteins defective in AGS are all associated with nucleic acid metabolism/ 
sensing. It is hypothesized that six of these proteins are involved in limiting the 
accumulation (TREX1, the three RNase H2 complex components, SAMHD1), or the 
nature (ADAR), of intracellular nucleic acid species, a failure of which process results in 
triggering an innate immune response that is more normally induced by viral nucleic 
acids. The seventh protein, IFIH1/MDA5, is also involved in nucleic acid metabolism, 
being a receptor for cytosolic dsRNA. This understanding defines a novel cell-intrinsic 
mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acids and 
offers an elegant mechanistic explanation for the phenotypic overlap of AGS with 
congenital infection and systemic lupus erythematosus (SLE). That is, in the absence of 
AGS-related protein activity, endogenous nucleic acids accumulate and are sensed as 
viral or “non- self,” leading to the induction of an interferon alpha-mediated immune 
response and, sometimes, the production of antibodies against self-nucleic acids. 
AGS is associated with increased levels of interferon alpha in the cerebrospinal fluid 
(CSF) and serum. However, interferon alpha levels, and white cell counts, in the CSF 
have been reported to fall over the first few years of life, perhaps corresponding with an 
apparent clinical “burning-out” of the encephalopathic period.  Unfortunately, due to the 
obvious difficulties of repeat CSF sampling, very few serial data are available (that is, 
systematic interferon alpha activity profiling beyond infancy has not been undertaken). 
Indeed, data acquired more recently on more than 200 AGS patients using qPCR 
analysis of interferon stimulated genes (ISGs) indicates the presence of a so-called 
“interferon signature” at any age in almost 100% of patients with mutations in TREX1, 
RNASEH2A, RNASEH2C, SAMHD1, ADAR, and IFIH1.  Around 30% of patients with 
RNASEH2B mutations demonstrated no such upregulation—but as ISG sampling in 
these studies was usually performed many years after initial diagnosis, it remains 
possible that most patients exhibit a positive interferon signature in the early stages of 
the disease. Whatever the case, these findings are important in indicating an ongoing 
biochemical disease process which is likely life-long in most patients. 
 
Most characteristically, AGS manifests as an early-onset encephalopathy that 
results in severe intellectual and physical handicap. A subgroup of infants with AGS 
present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver 
enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. 
Otherwise, most affected infants present at variable times after the first few weeks of 
life, frequently after a period of apparently normal development. Typically, affected 
infants demonstrate the subacute onset of a severe encephalopathy characterized by 
extreme irritability, a loss of previously acquired skills, and a slowing of head growth. 
Over time, as many as 40% develop chilblain-like skin lesions on the toes, fingers, and 
ears. Additional phenotypes are now being identified and include later onset disease 
after a year of age.19 Of specific note here, mutations in ADAR have recently been 
described in a clinically distinct phenotype characterized by bilateral striatal necrosis. 
Furthermore, mutations in RNASEH2B, ADAR and IFIH1 can cause non-syndromic 
spastic paraparesis in the presence of completely normal brain and spinal imaging, 
indicating that type I interferons can have a neurotoxic effect at the cellular level in the 

 
 
 
 
 
 
 
3
absence of obvious neuroimaging changes.  Most recently, IFIH1 gain-of-function 
mutations have been shown to cause a phenotype variably characterized by dental 
anomalies (early-onset periodontitis and root resorption), aortic and valvular 
calcification, glaucoma, psoriasis, contractures and acro-osteolysis20. 
Thus, although a minority of children are affected by the time of birth (that is, the 
disease has an in-utero onset), most experience the onset of disease at some point 
post-natally, often after a period of apparently normal development19. Moreover, disease 
progression is subacute, reflected in a progressive loss of skills occurring over several 
months. Thus, a window of opportunity exists during which treatments might be 
efficacious. Maximum benefit will likely be afforded when effective treatment is started 
as early as possible after disease onset. However, long-term/later-onset morbidities 
also occur, for example, chilblains, so children of any age might potentially benefit from 
efficacious treatment.  
 
1.2 
Name and Description of 
Investigational Product or 
Intervention 
Description of baricitinib, a JAK 
inhibitor and rationale for treatment 
The Janus Kinases (JAKs) 
are the principal family of kinases 
associated with signal transducers 
and activators of transcription 
(STAT) phosphorylation and 
activation21. The receptor-
associated STATs are 
phosphorylated by JAKs, resulting 
in their activation. Activated STATs 
are active transcription factors and 
drive the expression of multiple 
genes important for cell activation, 
localization, survival, and 
proliferation (Valentino and Pierre 
2006). The JAK/STAT pathway is 
used to transduce intracellular signals to relevant cell types following the binding of over 
40 different cytokines to their respective receptors (Valentino and Pierre 2006). 
Representative JAK/STAT- dependent cytokines involved in the inflammation 
associated with innate and adaptive immunity include type I and II interferons (IFNs), 
interleukin (IL)-2, IL-6, IL-12, IL-23, and granulocyte macrophage colony-stimulating 
factor. Evaluation of JAK inhibitors in clinical studies has validated JAK as a promising 
therapeutic target by demonstrating clinically meaningful efficacy in patients with 
rheumatoid arthritis and psoriasis22,23. JAK/ STAT pathway 21,24,25 inhibitors block 
downstream effects of IFN, preventing signaling after IFN receptor activation.   
Baricitinib is an orally administered JAK1/2 inhibitor which affects IFN type I 
receptors implicated in AGS. Since opening our expanded access use program for 
baricitinib, a JAK inhibitor (NCT01724580- hereafter referred to as JAGA), in 
Figure 2. Janus Kinase and IFN pathways. ssDNA- 
single stranded DNA, ssRNA- single stranded RNA, dsRNA- 
double stranded RNA, STING- stimulator of IFN genes, STAT- 
signal tranducers and activators of transcription, IRF3- 
Interferon regulatory factor 3, MAVS- Mitochondrial antiviral-
signaling protein 
 
 

 
 
 
 
 
 
 
4
February 2017, we have enrolled over twenty individuals. Preliminary data suggests 
improvement in patient reported scores and expression of IFN signaling genes. 
Baricitinib Nomenclature 
International Nonproprietary Name (INN): baricitinib 
Chemical Abstracts Service (CAS) Number: 1187594-09-7 
Lilly compound number: LY3009104 
Chemical name (International Union of Pure and Applied Chemistry [IUPAC]): 
2-(3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl) azetidin-3-yl) 
acetonitrile 
United States Adopted Names (USAN): baricitinib 
 
Chemical Structure 
 
1.3 Findings from Non-Clinical and Clinical Studies  
1.3.1 Non-Clinical Studies 
Please see the prescribing information for pre-clinical studies. 

 
 
 
 
 
 
 
5
1.3.2 Clinical Studies  
1.3.2.1 Human Pharmacokinetics 
PK values for dosing tables (Appendices 3 and 4) were generated from experience 
using baricitinib in adults as well as children with other genetic interferonopathies26. 
Additionally, preliminary data in our patient cohort demonstrated that PK values for AGS 
affected individuals with eGFR <120 were between 50-100 ng/ml for doses of 0.2-0.4 
mg/kg/day and for individuals with eGFR ≥120 were between 40-60 ng/ml for doses of 
0.2-0.4 mg/kg/day. The observed Cmax (roughly at 60-90 minutes post dose) at stable 
dose in these individuals is ~70 ng/mL. This corresponds to pediatric data in patients 
with other genetic interferon disorders studied at the National Institutes of Health, in 
whom at stable dose for the few patients with eGFR<120 ranged from 60-80 ng/mL, and 
for patients with eGFR ≥120 ranged from 50-70 ng/mL (communication from Eli Lilly). 
 
1.3.2.2 Clinical Studies in Adults 
Safety of Baricitinib in general clinical studies 
In clinical studies, baricitinib has been generally safe and well tolerated in single doses 
ranging from 1 mg to 40 mg and in repeat oral doses ranging from 1 mg to 20 mg.  
Extended safety of baricitinib from all patients exposed to any baricitinib dose (including 
non-approved doses) pooled from 9 clinical trials (one completed phase 1, three 
completed phase 2, four completed phase 3 and data through April 1, 2017, from one 
ongoing phase 3 long-term extension study).  
As of 13 August 2022, a total of 14,233 patients received baricitinib in clinical studies. 
Baricitinib has been approved for clinical use in adult patients in both the European 
Union and the United States. 
 
• The most commonly reported treatment-emergent adverse events (TEAEs) in 
patients with RA are upper respiratory infections, nausea, herpes zimplex, and 
herpes zoster.  
Figure 3:  PK values in children with AGS treated with baricitinib. Measurements at 1.5 hours post 
dose 
 
 
 

 
 
 
 
 
 
 
6
• The most commonly reported TEAEs in patients with COVID-19 are increases of 
liver enzymes, thrombocytosis, creatine phosphokinase increases, neutropenia, 
deep vein thrombosis, pulmonary embolism, and urinary tract infection. 
• The most common alterations in laboratory values involve neutropenia, platelet 
elevations, liver enzyme elevations, lipid elevations, and creatine phosphokinase 
elevations.  
• Some patients also had decreases in hemoglobin and white blood cells ([WBCs]; 
neutrophils and other white cell lines).  
• Adverse events of special interest include serious infections (including 
tuberculosus and opportunistic infections), malignancy, and thrombosis. The 
most common serious infections were pneumonia, herpes zoster, and urinary 
tract infections. 
• As part of the extended safety analysis, 3 individuals were noted to have a 
gastrointestinal perforation. 
• More information about the known and expected benefits, risks, and reasonably 
anticipated adverse events (AEs) may be found in the Prescribing Information. 
Information on AEs expected to be related to the investigational product may be 
found in Section 6 (Adverse Reactions) of the Prescribing Information.  
 
1.3.2.3 Clinical Studies in Children 
Safety of Baricitinib in AGS pediatric patients and dosing rationale. 
Overall, baricitinib was well tolerated by the AGS population. Over the duration of 
collected data, there were 49 hospitalizations in 22 subjects, all attributable to AGS and 
complications related to severe neurologic disease. This included urinary tract 
infections, seizures, admission for viral syndromes with respiratory distress or 
dehydration, pneumonia-including aspiration pneumonia, erythema multiforme, fracture, 
acute neurologic change, and planned interventions. One patient died during the 
enrollment phase, prior to drug initiation, from AGS-related complications. On study, 
one individual died secondary to pulmonary hypertension related to AGS while on study 
at day 42827. A second individual died after the data lock, while on study at day 1357. 
This death occurred in the context of a multisystem illness resulting in worsening 
pretreatment chronic liver failure with ascites and hypogammaglobulinemia, worsening 
of pretreatment pulmonary hypertension, leukopenia, anemia, worsening pretreatment 
thrombocytopenia requiring chronic steroids, and renal insufficiency. Autopsy revealed a 
fungal pneumonia, which had not been detected on pre-mortem cultures, and was 
possibly attributable to the study medication.  
Throughout the trial, dose adjustments were based on changes in weight, 
pharmacokinetic data, baseline eGFR and re-emergence of symptoms, according to the 
study protocol7,11. In most children, dose was stable or increased during the study. 
However, the medication was additionally decreased in several cases due to changes in 
laboratory parameters. In 4 children, drug dosage was decreased during the study 
period for BK viremia (n=1), thrombocytosis (n=2), anemia (n=1).   
Many individuals began the study with abnormal laboratory values (Table 1A). We used 
odds-ratios to compare the odds of having specific laboratory abnormalities on study 
versus at baseline (available data prior to drug) (Figure 4). After starting study 

 
 
 
 
 
 
 
7
medication, markers of liver dysfunction were transiently abnormal in a subset of 
subjects (ALT abnormal in n=10/35; AST n=20/35; GGT n=30/35), but overall improved 
on therapy (Table 1B). ALT decreased overall in treated subjects [estimated odds-ratio 
= .3 (95% CI = 0.2 to 0.5, Wilcoxon signed-rank test p = <0.005)]. After treatment, a 
decreased number of subjects met grade 3-4 severity criteria for GGT (n=4), ALT (n=1) 
and AST (n=1) abnormalities without statistical 
significance (Figure 4, Table 1B). 
 
Nineteen individuals had a grade 1-2 or greater 
anemia [estimated odds-ratio = 2 (95% CI 0.9-4.4, 
Wilcoxon signed-rank test p=0.086)] (Figure 4). One 
individual had a history of iron-infusion dependent 
anemia and required this therapy for grade 3 anemia 
(hemoglobin <8.0 g/dL) in the second year of 
treatment, at which point the dose was decreased. 
This was same individual who later died from 
infection.  
The majority (n=20/35) of subjects were found to 
have platelet abnormalities on study. The majority of 
these abnormalities represented an increase in 
platelet numbers, all grade 1-2 [estimated odds-ratio 
= 2.5 (95% CI = 1 to 6.1, Wilcoxon signed-rank test p 
= 0.043)] which resulted in decreased dosing in two 
individuals (Figure 4). Four individuals had Absolute 
Neutrophil Counts (ANC) that were transiently 
between 500-1000 cells/ul [estimated odds-ratio = 
5.8 (95% CI = 0.7 to 46.6, Wilcoxon signed-rank test 
p = 0.099)] (Figure 4). No individuals had decreases 
of the Absolute Lymphocyte Counts (ALC) <500 
during the reporting period [estimated odds-ratio = 
0.8 (95% CI 0.1-4.1, Wilcoxon signed-rank test 
p=0.746)] (Figure 4). 
Two individuals had reversible elevations of alkaline 
phosphatase after treatment, which were 
investigated and found to be consistent with transient 
hyperphosphatasemia of childhood, a common 
finding in this age group with no clinical significance. Two individuals had transiently 
elevated creatinine kinase. In general, creatinine and estimated glomerular filtration 
rates (eGFR) were stable during the study period and did not require dose adjustments 
after starting intervention.  
Five children received systemic steroids at prior to the study initiation for symptom 
management (n=3 for skin, n=1 for neurologic dysfunction, n=1 for thrombocytopenia), 
and these were decreased (n=2) or discontinued (n=3) by their local teams while on 
study. 
 
 
 
Figure 4. Odds-ratio 
calculations for safety 
parameters, comparing safety 
grades (abnormal versus 
normal) on study versus before 
study. Presented as Odds-Ratio 
with 95th percentile confidence 
interval; p-value for the Wald's 
test that the coefficient for on 
study is zero.  

 
 
 
 
 
 
 
8
Table 1. Safety Measures  
A. Maximum laboratory abnormalities prior to study 
Grade 
0 
1 
2 
3 
4 
Total 
Laboratory parameter 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N 
ABSOLUTE 
LYMPHOCYTES 
32 (94.1) 
2 (5.9) 
0 (0) 
0 (0) 
0 (0) 
34 
ABSOLUTE NEUTROPHILS 
31( 96.9) 
1 (3.1) 
0 (0) 
0 (0) 
0 (0) 
32 
LEUKOCYTOSIS 
32 (100) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
32 
LEUKOPENIA 
32 (91.4) 
3 (8.6) 
0 (0) 
0 (0) 
0 (0) 
35 
THROMBOCYTOSIS 
30 (96.8) 
1 (3.2) 
0 (0) 
0 (0) 
0 (0) 
31 
THROMBOCYTOPENIA 
30 (88.2) 
3 (8.8) 
1 (2.9) 
0 (0) 
0 (0) 
34 
ALANINE 
AMINOTRANSAMINASE 
(ALT/SGPT) 
18 (51.4) 
15 (42.9) 
1 (2.9) 
1 (2.9) 
0 (0) 
35 
ALKALINE PHOSPHATASE 
(AP) 
34 (100) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
34 
ASPARTATE 
AMINOTRANSAMINASE 
(AST/SGOT) 
14 (40) 
20 (57.1) 
1 (2.9) 
0 (0) 
0 (0) 
35 
CHOLESTEROL 
31 (88.6) 
3 (8.6) 
1 (2.9) 
0 (0) 
0 (0) 
35 
CPK 
32 (94.1) 
3 (5.9) 
0 (0) 
0 (0) 
0 (0) 
34 
CREATININE 
24 (68.6) 
11 (31.4) 
0 (0) 
0 (0) 
0 (0) 
35 
GAMMA GLUTAMYL 
TRANSFERASE 
14 (40) 
12 (34.3) 
6 (17.1) 
3 (8.6) 
0 (0) 
35 
HEMOGLOBIN 
29 (82.9) 
6 (17.1) 
0 (0) 
0 (0) 
0 (0) 
35 
RETICULOCYTE COUNT 
16 (47.1) 
18 (52.9) 
0 (0) 
0 (0) 
0 (0) 
34 
TRIGLYCERIDES 
25 (71.4) 
9 (25.7) 
1 (2.9) 
0 (0) 
0 (0) 
35 
eGFR 
29 (82.9) 
6 (17.1) 
0 (0) 
0 (0) 
0 (0) 
35 
Total 
391 (75.5) 
112 (21.6) 
11 (2.1) 
4 (0.8) 
0 (0) 
518 
 
B. Maximum laboratory abnormalities on study 
Grade 
0 
1 
2 
3 
4 
Total 
Laboratory parameter 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N 
ABSOLUTE 
LYMPHOCYTES 
27 (77.1) 
8 (22.9) 
0 (0) 
0 (0) 
0 (0) 
35 
ABSOLUTE NEUTROPHILS 
14 (40.0) 
16 (45.7) 
5 (14.3) 
0 (0) 
0 (0) 
35 
LEUKOCYTOSIS 
35 (100) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
35 
LEUKOPENIA 
20 (57.1) 
11 (31.4) 
4 (11.4) 
0 (0) 
0 (0) 
35 
THROMBOCYTOSIS 
15 (44.1) 
15 (44.1) 
3 (8.8) 
1 (2.9) 
0 (0) 
34 
THROMBOCYTOPENIA 
30 (88.2) 
3 (8.8) 
1 (2.9) 
0 (0) 
0 (0) 
34 
ALANINE 
AMINOTRANSAMINASE 
(ALT/SGPT) 
13 (37.1) 
21 (60) 
0 (0) 
0 (0) 
1 (2.9) 
35 
ALKALINE PHOSPHATASE 
(AP) 
27 (77.1) 
6 (17.1) 
0 (0) 
2 (5.7) 
0 (0) 
35 

 
 
 
 
 
 
 
9
ASPARTATE 
AMINOTRANSAMINASE 
(AST/SGOT) 
0 
30 (85.7) 
4 (11.4) 
1 (2.9) 
0 (0) 
35 
CHOLESTEROL 
21 (60) 
13 (37.1) 
0 (0) 
0 (0) 
1 (2.9) 
35 
CPK 
18 (51.4) 
12 (34.3) 
4 (11.4) 
1 (2.9) 
0 (0) 
35 
CREATININE 
13 (37.1) 
22 (62.9) 
0 (0) 
0 (0) 
0 (0) 
35 
GAMMA GLUTAMYL 
TRANSFERASE 
5 (14.3) 
20 (57.1) 
6 (17.1) 
4 (11.4) 
0 (0) 
35 
HEMOGLOBIN 
15 (42.9) 
13 (37.1) 
6 (17.1) 
1 (2.9) 
0 (0) 
35 
RETICULOCYTE COUNT 
3 (8.6) 
32 (91.4) 
0 (0) 
0 (0) 
0 (0) 
35 
TRIGLYCERIDES 
17 (48.6) 
13 (37.1) 
5 (14.3) 
0 (0) 
0 (0) 
35 
eGFR 
19 (54.3) 
16 (45.7) 
0 (0) 
0 (0) 
0 (0) 
35 
Total 
226 (43) 
249 (47.4) 
38 (7.2) 
10 (1.9) 
2 (0.4) 
525 
 
 
Additional Safety Monitoring- Cardiac and Pulmonary Hypertension Monitoring 
Pulmonary hypertension (PH) is a rare but potentially fatal disorder characterized 
by severe vasculopathy and elevated pulmonary artery pressures leading to right-sided 
heart failure. Progressive PH has both genetic and inflammatory influences 28-34. In 
particular, type I interferons, as are overexpressed in AGS, have been established as 
risk factors for the development of PH 29,35-38. We have identified several individuals 
within our cohort with PH, as related to systemic interferon overexpression27. Cardiac 
involvement will be quantified using clinical assessment and echocardiogram. 
Individuals affected by AGS will have clinical cardiac evaluations every other year, with 
additional management as clinically indicated. In the patients identified as being 
affected by PH, we will follow the relationship between PH and the response to 
baricitinib. 
 
1.4 Selection of Drugs and Dosages 
Dosing formulations in use in this study will be limited to the 1 and 2mg tablets and will 
be used without splitting. Dispersion will be permitted to aid in administration based on 
IND data submitted to the FDA by Eli Lilly with a letter of cross-reference and according 
to recently updated product information. Administration is also allowed via clinically 
placed gastrostomy feeding tube (G-tube) or nasogastric tube, as well as via oral 
dispersion for patients who are unable to swallow whole tablets. Guidance for 
alternative administration for participants unable to swallow whole tablets is available in 
the Olumiant package insert. 
As the FDA-approved dose in adults with rheumatoid arthritis is 2 mg each day, the 
rationale for the starting dose in the AGS subjects and dose modification guidelines are 
detailed in protocol Section 4.3.  
 
Dosing tables will be based on PK studies conducted by Eli-Lilly and are provided in 
Appendices 3 and 4. 
  

 
 
 
 
 
 
 
10
1.5 Relevant Literature and Data 
AGS is a monogenic disorder resulting from loss-of-function (except in the case of 
IFIH1) mutations in any of several distinct genes, resulting in a type 1 interferonopathy 
associated with both peripheral manifestations and devastating neurologic 
consequences. Given that AGS is an interferon-mediated disease, patients with AGS 
are expected to benefit from JAK1 and JAK2 inhibition and, thus, it may be beneficial to 
treat them with baricitinib. The purpose of this clinical trial is to establish whether 
baricitinib can be effectively used to treat children affected by AGS. 
Measurement of Clinical Diary Scores 
As interferon levels can fluctuate daily in individuals 
affected by AGS, we have established a daily self-
measure of systemic inflammation, the daily AGS 
symptom diary (Figure 5 and Appendices 5 and 6). 
This clinical diary has been in use in the Lilly-
sponsored expanded access program for the JAK 
inhibitor baricitinib (NCT01724580, JAGA) since 
February 2017. As part of the protocol, each patient 
or patient-proxy completes a daily assessment of 
symptomatology. This includes a minimum of 2 
weeks of baseline daily scores, daily reports while 
on study drug, and in the case of drug cessation, an 
additional 28 days of diary entries. Two forms of the 
diary are offered: paper and electronic, as administered through REDCap. The diary 
allows for daily assessment of systemic signs of inflammation, and includes family-
based assessment of irritability, skin findings, and hyperthermia (Appendices 5 and 6). 
The clinical diaries have shown to be responsive to baricitinib (Figure 5). The diary 
scores will be further validated against other outcome measures, as described below. 
 
Measurement of IFN signaling 
gene scores 
IFN scores are based on mRNA 
expression of IFN signaling genes 
(ISG) and represent a surrogate 
marker for autoinflammation in a 
variety of disorders 39-41. IFN 
scores based on mRNA 
expression of ISGs have been 
used to assign a severity score of 
autoinflammation in a variety of 
disorders, including AGS 4 and 
systemic lupus erythematous 39,40. 
We measured ISG in individuals 
affected by AGS as per 
established protocol 4,42,43. ISG 
Figure 6: ISG based IFN score. In left panel, elevated IFN 
signaling gene scores (ISG) in AGS (n= 180 samples) and controls 
(n=104), with significant increases across all AGS genotypes. In right 
panel, response of this score to treatment with baricitinib (in 12 affected 
individuals with paired results at baseline and at 4 hours post dose 72 
hours after drug initiation). Although ISG scores do not normalize, they 
are decreased from pre-treatment scores (Mann-Whitney, p<0.001). 
Based on existing data in our laboratory, this approach has a sensitivity 
of 89.86% (95% CI 83.83-94.22) and specificity of 82.61% (95% CI 
73.30-89.72). 
 
Controls
All genotypes
TREX1
RNASEH2A
RNASEH2B
RNASEH2C
SAMHD1
ADAR1
IFIH1
-20
0
20
40
60
80
IFN score controls versus AGS by genotype
IFN score
***
***
***
**
***
***
***
***
*** p<0.0001
**  p<0.001
baseline
3 days
control
-20
0
20
40
60
80
IFN score
IFN score by time on baricitinib
***
***
***p<0.0001
Figure 5:  Clinical symptom diary score 
in AGS affected individuals and 
improvement on treatment. 
 
0
50
100
0
5
10
weeks on baricitinib
clinical score

 
 
 
 
 
 
 
11
scores were calculated for all AGS affected individuals in the MDBP registry with 
available blood samples (180 AGS samples and 104 control samples) as per 
established methodology 4,42-44. Preliminary data on this measure demonstrates an 
improvement in ISG scores in children with AGS before and after treatment with 
baricitinib (Figure 6). 
 
Measurement of Neurologic Function based on GMFM-88 
Individuals affected by AGS can have a 
range of motoric disability, secondary to 
direct muscle inflammation (inflammatory 
myopathy) as well as from injury to the 
central nervous system. As physical abilities 
are an essential component of activities of 
daily living and a major contributor to quality 
of life, it is important to assess the impact of 
AGS on motor function. Gross Motor 
Function Measure (GMFM-88) is a validated 
outcome measure of motor function in 
children 45-51. Depending on the tracts 
involved and the extent of injury, individuals 
affected by AGS can have a range of 
motoric disability from mild lower extremity 
spasticity to inability to support one’s own 
head. The GMFM-88, administered by trained physiotherapists, covers 5 distinct 
categories: lying and rolling, sitting, crawling and kneeling, standing, and walking and 
running. While there are few published studies measuring ambulation and motoric 
decline in patients with a leukodystrophy, our goal is that these longitudinal motor 
assessments will aid our understanding of disease progression and facilitate the 
assessment of drug response. In addition to its initial use in cerebral palsy, GMFM-88 
has been utilized across  several other disorders, including metachromatic 
leukodystrophy 52, trisomy 21 53, and spinal muscular atrophy 54. Preliminary data 
demonstrates the feasibility of GMFM-88 in individuals affected by AGS (Figure 7) and 
responsiveness to therapy. However, during our pilot studies, we determined a 
significant floor effect in AGS patients using the GMFM-88, with measurable function 
above 15% of normative values in only a small subset of individuals. Similarly, only a 
small subset of invididuals had measureable improvement in GMFM-88 during a study 
period of 6 months or more.  
 
Measurement of AGS Scale 
In order to account for these floor effects, in addition to measurement of motor function 
through the GMFM-88, we will also employ an AGS Scale, which was recently 
developed by our group.55,56 Progressive childhood diseases, such as AGS, offer 
unique complications in that they require the assessment of children with potentially 
worsening skills superimposed on an evolving panel of predicted developmental 
Figure 7:  Domain scores for GMFM-88 in 15 
children affected by AGS demonstrate the best skills 
in lying and sitting, and severe deficits in crawling, 
standing, and walking (left panel). A subset of 
affected individuals develop improvement after 
treatment with baricitinib (right panel) 
Lying/rolling
Sitting
Crawling
Standing
Walking/running
Average
0
50
100
Score (%)
GMFM-88 
baseline
6 months
0
10
20
30
40
50
Time on JAK1/2 (month)
GMFM-88 score

 
 
 
 
 
 
 
12
milestones (Figure 8A). This scale allows for assessment of  skills (smiling, head 
control, rolling) as compared to a historical data set of children affected by AGS.  
Preliminary data using the AGS scale (Appendix 5, Figure 8B), demonstrates 
responsiveness in our expanded access program in a proportion of individuals. In our 
compassionate cohort, 11/34 (32%) treated individuals with data available for AGS 
scale scoring had improvement in the AGS scale after treatment with baricitinib. 
Response was correlated with AGS scale score at baseline (Table 2) such that in 
individuals with an AGS scale of 0-3 (Cohort A in proposed study), 6/19 individuals 
improved (31%), while in those individuals with AGS scale of 4-8 (Cohort B), 5/6 
individuals improved by 2 points (83%) and the remaining individual also improved, but 
only by one point. Notably, none of higher functioning individuals at the upper level of 
the AGS scale (>9) (0/9) had improvement on the AGS scale, although this could be 
attributed to ceiling effect. Notably, some higher functioning individuals (Cohort C) had 
measurable improvement in GMFM-88, in particular in domain E (walking, running and 
jumping). This scale is simple enough to be able to be applied retrospectively, based on 
clinical notes, permitting us to develop a historical control cohort for comparison.  
Figure 8A. Developmental milestones are 
severely delayed in AGS. Individuals affected by 
AGS are profoundly disabled, with limited functional 
skills across modalities. 
0
20
40
smiling
head control
hands together
reaching
roll over
mama dada non specific
sitting no support
stand holding on
thumb finger grasp 
one word
pull to stand
get to sitting
two words
stand alone
walk alone
Months
Developmental milestone
P10
P25
P50
P75
P100
Figure 8B. Pilot data using AGS Scale; AGS scale 
scores improve following treatement with baricitinib 
in a majority of individuals.  
 
 
 
 
 
 

 
 
 
 
 
 
 
13
Measurement of Skin involvement using a standardized scale, the CLASI 
As one of the most clinically measurable manifestations of AGS is the dermatologic 
involvement, we have initiated a project to define and quantitate the skin manifestations 
found in patients with AGS. Aside from neurologic injury, skin manifestations are one of 
the most common manifestations of AGS, occurring in over 30% of affected individuals 
2. Skin manifestations in AGS are reminiscent of those seen in other rheumatologic 
disorders, such as systemic lupus erythematosus (SLE). Skin injury can present 
variably (Figure 9A-C) and appear uniquely responsive to JAK1/2 inhibitors (Figure 9D). 
The skin ulcerations and chilblains found in individuals affected by AGS are 
hypothesized to be secondary to an underlying vasculopathy 57-59. These skin lesions 
have previously been unresponsive to treatment with steroids or other immune 
suppressive approaches 2 and anecdotal evidence of their improvement with treatment 
with JAK1/2 inhibitors are a major argument for clinical benefit using these drugs. In 
addition, they offer a readily accessible tissue that can be tested for IFN related injury, 
unlike brain tissue. For this study, investigations will utilize the assessment tool CLASI 
(Cutaneous Lupus Erythematosus Disease Area and Severity Index- Appendix 13) 
before and after treatment with JAK1/2 inhibitor 60.  
The connection between skin pathology and IFNs is well established. A single injection 
of IFN into human skin activates over 700 genes, including multiple chemokines 61. 
These IFN-regulated gene products are also up-regulated in chronic inflammatory skin 
diseases such as atopic dermatitis, psoriasis, and cutaneous lupus. Additionally, 
treatment of psoriasis with a JAK1/3 inhibitor, tofacitinib, results in the resolution of 
cutaneous inflammation over a 12-week period 62. As determined by histology and gene 
expression measures, this improvement is associated with progressive normalization of 
IFN-regulated genes, as well as other immune pathways which are indirectly stimulated 
by IFN activation 62. Within one month of treatment with tofacitinib, histologic disease 
features and infiltrating T-cells and DCs are significantly reduced and several IFN-
regulated gene products show >10-fold reductions 62. As hypothesized, in preliminary 
data, the skin manifestations in AGS have been robustly responsive to baricitinib 
therapy (Figure 9). 
 
 
 
 
 
 
 
 
 
 
Figure 9. Dermatologic findings in AGS 
 
A. Chilblain 
lesions or pernio
may be over the 
hands, feet and 
ears in affected 
individuals
B. More 
diffuse 
panniculitis 
may be seen 
over the 
trunk or 
extremities
C. Non-specific 
eczematous-
like lesions in 
may be seen 
over neck and 
flexor regions
D. Resolution 
of life long skin 
abnormalities 
in same child 
as C. 72 hours 
after baricitinib
initiation

 
 
 
 
 
 
 
14
1.6 Compliance Statement 
This study will be conducted in full accordance with all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state 
laws and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312, 314 and 812. 
All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent, and will report unanticipated problems involving risks to subjects or others in 
accordance with The Children’s Hospital of Philadelphia IRB Policies and Procedures 
and all federal requirements. Collection, recording, and reporting of data will be 
accurate and will ensure the privacy, health, and welfare of research subjects during 
and after the study.  
 
2 
STUDY OBJECTIVES 
This study is an open-label design using baricitinib in patients with AGS. Subjects 
will be compared to pretreatment values and historical controls before and after 
treatment with baricitinib for AGS scale results. Secondary outcomes will also include 
functional neurologic tests, symptom diary scores, safety parameters and clinical 
features including skin involvement, and ISG scores. Though the open-label design has 
potential for the introduction of bias, the study design represents an ethical approach for 
treatment of AGS given the treatment effect seen in a prior Lilly-sponsored expanded 
access approach. 
 
2.1 Primary Objective (or Aim) 
The primary objective of this clinical study is to determine if the administration of 
baricitinib to patients with AGS results in improvement or stability of the AGS scale from 
baseline to 52 weeks after treatment.  
 
2.2 Secondary Objectives (or Aim) 
Secondary objectives for this study include: 
 
Determine if the administration of baricitinib to patients with AGS results in an 
improvement or stability of the AGS scale from baseline through end of study treatment, 
up to 288 weeks. 
 
Secondary objectives also include assessment of safety parameters including 
laboratory findings and adverse events.  
 
An additional secondary objective is to determine if the administration of baricitinib to 
patients with AGS results in improvement of the AGS disease activity scale (daily diary), 
and of the GMFM-88 post-baseline for up to 288 weeks.  
 
Additional secondary objectives include: 
• the stability or improvement of known clinical complications of AGS, including 
skin manifestations as measured by the CLASI (Cutaneous Lupus Assessment 

 
 
 
 
 
 
 
15
of Skin Involvement), 
• the improvement of a surrogate biomarker, the Interferon Stimulatory Genes 
(ISG) score, as calculated by Nanostring analysis. 
 
 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
3.1.1 Transfer of patients from the Compassionate Use Treatment Protocol I4V-
MC-JAGA 
Subjects enrolled in the Compassionate Use Treatment Protocol I4V-MC-JAGA (JAGA 
Compassionate Use study, CHOP IRB Study #13205), sponsored by Eli-Lilly, and for 
whom commercial supply is not available, may be reconsented to the investigator-
initiated JAK inhibitor treatment in AGS study. Because the JAGA Compassionate Use 
study protocol and this protocol are carefully aligned, subjects will continue with the next 
study visit in their study schedule as planned, as part of their original participation in the 
JAGA Compassionate Use study. For example, if subjects recently completed visit 212, 
and are next due for visit 213 three months later, they will complete visit 213 as part of 
their participation in the investigator-initiated JAK inhibitor treatment in AGS study, 
without any interruption in the sequence of study visits. 
 
3.1.2 Additional subjects 
3.1.2.1 Screening Phase 
Participants will be recruited by advertisement via testing laboratories, family advocacy 
organizations, self-referral, or participation in a clinical leukodystrophy program. 
Patients’ families will be first contacted by non-study personnel to discuss the possibility 
of participating in a clinical trial. If the patient is also a patient of the investigators, study 
participation will be discussed with the Medical Monitor. Should the family be interested, 
patients and families will be invited to contact the investigative team to discuss 
participation and ICF documents will be shared with the family. Should the family 
continue to be interested, the family will be invited to visit CHOP.  
Potential subjects will be screened using the protocol inclusion and exclusion criteria. 
Potential subjects can also be pre-screened over the phone. The pre-screening period 
is described in Section 4.2. As part of the pre-screening period, patients or their 
guardians will undergo telephone consent, to explain the purpose and procedure of the 
study. Formal written consent will be obtained at Visit 1. Medical records will be 
collected for verification of study eligibility, including mutation status, after release of 
information and after verbal consent for screening. Parental/guardian permission 
(informed consent) will be obtained prior to any study related procedures being 
performed. Physical examination, echocardiogram, EKG, CXR, baseline neurologic 
function testing, and blood samples will be drawn to confirm eligibility based on clinical 
laboratory parameters. Additional results of blood tests for hematologic, liver, and 
metabolic parameters will be performed on a research basis for screening purposes. 
Females after menarche will have a urine pregnancy test.  
 

 
 
 
 
 
 
 
16
3.1.2.2 Study Treatment Phase (start of the study intervention) 
Eligible patients will be enrolled and initiated on intervention, baricitinib, using open-
label treatment, and according to established dosing regimens for weight and eGFR 
based on age (Appendices 3 and 4). Regular evaluations for safety and efficacy 
(Appendices 1 and 2) will be performed while on study intervention (see section 4). 
 
3.1.3 Allocation to Treatment Groups and Blinding 
This is an unblinded, open-label study. A historical cohort will be used for comparison of 
the natural history of the AGS Scale. 
 
3.2 Study Duration, Enrollment and Number of Sites 
3.2.1 Duration of Study Participation 
The study duration per subject will be up to 288 weeks, preceded by a screening period 
during which baseline testing will be obtained.  
Study duration will be extended beyond Week 288 to long term follow up if transition to 
commercial supply is not possible for the patient.  
 
3.2.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at one investigative site in the United States. 
It is expected that up to approximately 55 subjects may be enrolled, including those 
patients transferred from the JAGA Compassionate Use study (CHOP IRB Study 
#13205).  
 
3.3 Study Population 
Patients who meet all of the inclusion criteria (Section 3.4.1) and do not meet any of the 
exclusion criteria (Section 3.4.2) may enter the study (that is, sign consent). In addition, 
patients must meet the enrollment criteria in order to be eligible to receive baricitinib.  
The enrollment number of up to approximately 55 is an estimate based on the number 
of subjects required to obtain statistically significant results for efficacy, and accounting 
for those subjects who are found to be ineligible at screening, subjects withdrawn from 
participation for various reasons and replaced. The analysis of data obtained from these 
initially ineligible, but prospectively approved group of subjects entered to the study, will 
be assessed independently of the main group of subjects who meet all eligibility criteria. 
The impact of this group of subjects on the statistical analysis of this clinical protocol 
has been added to Section 6.4, “Sample Size and Power”.  
 
3.3.1 Patients from the Compassionate Use Treatment Protocol 14V-MC-JAGA 
Patients previously enrolled in the Compassionate Use Treatment Protocol I4V-MC-
JAGA (JAGA Compassionate Use study, CHOP IRB Study #13205) will automatically 
roll into this study and do not need to meet the eligibility criteria outlined below. 
 
3.3.2 Inclusion Criteria 
Identification of individuals appropriate for the study 

 
 
 
 
 
 
 
17
Eligible patients will meet the following criteria: 
o Clinical or molecular identification of Aicardi Goutières Syndrome including the 
following features 
o CSF or blood markers suggesting elevations of markers of interferon 
activation including CSF pleocytosis, elevation of interferon, and/or 
neopterin and tetrahydrobiopterin elevations 
o Evidence of neurologic disease on neuroimaging including intracranial 
calcifications and or a leukoencephalopathy 
o Clinical features of disease including features such as microcephaly, 
subacute encephalopathy, myopathy, spastic diplegia, skin involvement, 
autoimmune hepatitis, hematologic abnormalities 
o OR have documented mutations felt to be pathogenic in an AGS 
associated gene. 
o Are ≥1 month of age.  
o Are ≥4.5 kg in body weight.  
o 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.  
o Parental/guardian permission (informed consent). 
 
3.3.2.1 Inclusion of Minorities and Children 
The disorders to be investigated affect both genders and all different ethnic groups and 
we therefore expect to have proportional representation among the participants of the 
trials. These are rare disorders, and we will attempt to recruit all presenting potentially 
eligible patients. Most persons affected with AGS are children and thus pediatric patients 
will be included. 
 
3.3.3 Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
o Are pregnant or nursing at the time of entry or unable to use contraception as 
detailed below 
o 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 
o 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. 
o 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 

 
 
 
 
 
 
 
18
• 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) 
o Overall health status that in the opinion of the investigator limits the safety of the 
use of baricitinib. 
o 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. 
o Have the following evidence of renal insufficiency: 
o 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.  
o 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.  
o 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. 
o Have any of the following specific Hematologic abnormalities on screening 
laboratory tests (Appendices 10, 11, 12): 
o Hemoglobin <7 mg/dL (70 g/L). In infants <2 mo of age, 8 mg/dL 
will be used as a threshold 
o Neutropenia (absolute neutrophil count [ANC] <500 cells/µL)  
o CD4 <250 cell/l on lymphocyte subset testing (where Absolute 
CD4 count=Absolute CD3/CD4 count=CD3/CD4 count=CD4 
count=Absolute CD3+CD4+ cells) 
o Thrombocytopenia (platelets <30,000/µL). Patients who are on 

 
 
 
 
 
 
 
19
anticoagulation or having a history of life-threatening bleeding 
should be excluded if platelet count is <50,000/µL  
o 
Have any of the following infectious risks:    
o 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  
o Ongoing or incompletely treated severe or systemic infection, 
excluding cellulitis/osteomyelitis that is felt to be attributable to AGS 
o Have had symptomatic herpes zoster infection within 12 weeks 
prior to entry or during the screening period 
o Have a history of disseminated/complicated herpes zoster (for 
example, multidermatomal involvement, central nervous system 
involvement or systemic involvement including hepatitis or 
pneumonitis) 
o Have a history of active hepatitis B, hepatitis C, or human 
immunodeficiency virus (HIV) 
o Have had household contact with a person with active tuberculosis 
(TB) and did not receive appropriate and documented prophylaxis 
for TB 
o 
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. 
o 
Have liver abnormalities consistent with severe, chronic liver disease (Appendix 
9). 
o 
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 
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; 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. 
o 
Are unable or unwilling to make themselves available for the duration of the 
study and/or are unwilling to follow study restrictions/procedures. 
o 
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.  
o 
Have received or be currently treated with BCG (Intravesical), Cladribine, 
Dipyrone, Pimecrolimus, and Tacrolimus (Topical). 

 
 
 
 
 
 
 
20
o 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.  
o 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. 
o 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. 
o 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? 
 
o 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. 

 
 
 
 
 
 
 
21
o Have hepatitis C virus (positive for anti-hepatitis C antibody with confirmed 
presence of hepatitis C virus). 
o 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. 
o Have HIV virus. In infants <12 months of age, maternal testing can be used 
instead of testing the patient. 
o Taking a concomitant medication on the list of exclusion criteria (Appendix 16). 
 
 
4 
STUDY PROCEDURES 
4.1 Unforeseeable emergency events 
In some circumstances, unforeseeable events, such as public health emergencies, 
states of emergency related to civil unrest, or weather emergencies, or individual health 
emergencies (affecting the patient or a caregiver), may create situations where it is 
unsafe for patients and their families to travel to the study site for in-person 
assessments. In that case, the visit will be conducted using video operations. The 
changes from an in-person evaluation, including differences to the study outcome 
collection, will be reported as a minor protocol deviation to the IRB at the time of 
continuing review. 
 
4.2 Pre-screening period 
The pre-screening period is applicable only to subjects not transferred from the JAGA 
Compassionate Use study (CHOP IRB Study #13205). The pre-screening period is a 
period from 2 weeks to 6 months during which the study will be discussed with the 
patient and caregivers. During this time, the study team may discuss the study with 
patients and families, and records of clinically indicated studies will be collected to help 
determine potential eligibility during the screening process. Individuals will undergo this 
pre-screening period if insufficient information about prior clinical care is available to the 
study team, for example, if their clinical care is received outside of the regional area. As 
part of the pre-screening period, patients or their guardians will undergo telephone 
consent, to explain the purpose and procedure of the study. Formal written consent will 
be obtained at Visit 1. During this period, blood and urine will be collected and daily 
diaries completed. 
 
4.3 Screening Visit 
Screening (Visit 1) is applicable only to subjects not transferred from the JAGA 
Compassionate Use study (CHOP IRB Study #13205). The screening visit is a 2- to 28-
day period beginning at Visit 1. After receiving written informed consent from the 
patient’s parent or a legal guardian (hereafter, “parent” refers to “parent or legal 
guardian”), patients will be assigned a patient number and will be considered entered 
into the study and study procedures may begin. Entry procedures will be performed per 
the Study Schedule (Appendices 1 and 2). During the screening period, patients must 

 
 
 
 
 
 
 
22
complete at least 14 days of diary entries before receiving the first dose of baricitinib 
(refer to the Patient Diary and Diary Score section below and Appendices 5 and 6). 
Current use of concomitant medications and reasons for use will also be collected on 
the eCRF, as well as start and stop dates. Particular note will be made of medications 
that are contraindicated (see Section 3.4.2) and which require dose adjustment (see 
Section 4.4). 
 
4.4 Study Treatment Phase 
4.4.1 Enrollment 
Consent 
Written informed consent from the patient/patient’s parent or a legal guardian will be 
obtained in person by the study investigators prior to any study procedure, with the 
exception of blood and urine tests, and daily diaries, which may be completed from the 
pre-screening period, after verbal consent. 
For the patients transferred from the JAGA Compassionate Use study (CHOP IRB 
Study #13205), written informed consent from the patient/patient’s parent or a legal 
guardian will be obtained by the study investigators prior to any study procedure 
completed as part of this investigator-initiated study. 
Additionally, all the JAGA subjects (including the patients who do not consent and 
transition to the investigator-initiated JAK inhibitor treatment in AGS study will be asked 
to sign a consent form to allow for their data collected as part of the compassionate use 
program to be used for data analysis as part of the investigator-initiated study. The 
JAGA subjects who do not transition to the investigator-initated study will sign a 
separate consent form while the subjects who transition will be re-consented with a 
revised informed consent form including mention of this data transfer. Statistical 
considerations of this data transfer are detailed in Section 6. 
 
Inclusion criteria 
Entered patients are eligible for enrollment into the study (that is, eligible to receive 
baricitinib) only if they meet inclusion criteria (Section 3.4.1) at the time of Visit 2 and  
don’t meet the exclusion criteria listed in Section 3.4.2. 
 
Exclusion from Study Enrollment 
Entered patients are ineligible for enrollment (that is, ineligible to receive baricitinib) and 
should be discontinued from the study if they meet any of the exclusion criteria listed in 
Section 3.4.2. 
 
Patients who are entered, but do not meet enrollment criteria, should be discontinued 
from the study. These patients can be re-entered into the trial (that is, be reconsented) if 
the investigator believes that the patient might meet enrollment criteria at a future date, 
taking into consideration the volume of blood required for rescreening. Patients will 
receive treatment as clinically indicated for infections regardless of treatment decisions 
for baricitinib. 
 

 
 
 
 
 
 
 
23
Rationale for Exclusion of Certain Study Candidates 
Exclusion Criterion excludes individuals with concomitant medical conditions that 
increase the risk for their participation in the study, who may not be compliant with 
study-related procedures or whose participation in the study may introduce bias.  
 
Discontinuation of patients after enrollment if criteria are not met 
The criteria for enrollment must be followed explicitly. If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient should be discontinued from the 
investigational product, but may be allowed to continue in the study in order to provide 
the follow-up data.  
 
4.4.2 Initial Treatment and Dose Escalation 
Baricitinib will be dosed by patient age, weight range and eGFR. See Appendix 3 for the 
dosing schedule for patients with eGFR ≥60 mL/min/1.73 m2 or normal eGFR for 
patients age <24 months (eGFR ≥60 mL/min/1.73 m2). 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. 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. 
Tolerance will be judged by stability or improvement in hematology and chemistry 
laboratory test results collected as specified in Study Schedule (Appendices 1 and 2).  
See Appendix 4 for the dosing schedule for patients with eGFR 30 - <60 mL/min/1.73 
m2 or patients <24 months with abnormal eGFR (eGFR 30 - <60 mL/min/1.73 m2).   
Patients must receive a dose for at least 72 hours before a dose escalation can occur. 
Safety laboratory data will be assessed according to the Study Schedule (Appendices 1 
and 2). 
Every effort should be made to follow the dose escalation schedule shown in 
Appendices 3 and 4. However, if a patient’s condition warrants an accelerated dose 
escalation schedule, dose reduction, interruption, or discontinuation, this may be 
allowed after review of the patient’s clinical data and consultation with the sub-
investigators. Additionally, in the event of AEs possibly attributable to the study drug, 
the dose may need to be reduced. These decisions should be taken following 
documented consultation, and agreement between the investigator and sub-
investigators, and approval from the IRB prior to initiating the dose modification. Only in 
emergency situations will the investigator take subsequent dose restarts or increments 
after review of clinical data, documented agreement between the investigator and sub-
investigators, and notification of the IRB. 
Attention will be given to concomitant medications, in particular those that are exclusion 
criteria (Appendix 16). 
Where needed, clinical pharmacists will be contacted about the need for dose 
adjustment and for guidance related to concomitant therapies that must be used with 
caution.  

 
 
 
 
 
 
 
24
In the event that it is necessary to contact a clinical pharmacist, the study team can 
page the 24/7 on-call clinical pharmacist. 
 
Pharmacokinetic Sampling: Blood samples will be collected to determine baricitinib 
concentrations. Samples will be collected after beginning baricitinib therapy and at each 
dose increase at the time points shown in the Study timeline and may be collected at 
each study visit for safety monitoring. In these cases, PK sampling will occur at least 72 
hours after dosing changes or at the next visit. PK testing may include a single 
measurement at 1.5 hours, or a full PK series at baseline, 1.5 hours and 4 hours post 
dose, and may include several doses during the day (eg morning and afternoon dose). 
For PK series, an IV will be placed. For single PKs, these will be drawn with the safety 
laboratory monitoring. PK samples may be banked for later analysis. 
As PK data become available, dosing adjustments may be required.  
Finally, changes in a subject’s weight or renal function may require dose changes as the 
individual falls within different categories in the tables in Appendices 3 and 4. For 
example, this may occur in a child under 1 year of age with rapid weight gain. 
 
4.5 Continuing treatment 
4.5.1 Continuing treatment for patients transferred from the JAGA 
Compassionate Use study 
After consent to the investigator-initiated JAK inhibitor treatment in AGS study, 
transferred patients will undergo review of the patient’s clinical condition, AEs, and 
blood tests for safety by the Principal Investigator. Safety laboratory assessments will 
be reviewed by the investigator along with a copy of the patient’s diary, AEs and 
concomitant medications. If the patient is responding adequately to treatment (average 
diary score <0.5) or reduction in average diary score, the patient will continue receiving 
baricitinib therapy with follow-up appointments according to the Study Schedule 
(Appendices 1 and 2), based on the timelines of the most recent study visit on the JAGA 
Compassionate Use study (CHOP IRB Study #13205). If the patient is responding to 
treatment, but has not yet reached symptom control, dose escalation may be performed 
as discussed above and in Appendices 3 and 4. Once the patient has reached a stable 
dose of baricitinib, the same total dose may be administered as equal or unequal 
divided doses (administered up to 4 doses in a day [24 hours]).  
 
4.5.2 Continuing treatment for patients originally consented to this study 
After the patient has received baricitinib at the target dose level, the patient will have an 
evaluation performed, which will include an assessment of the patient’s clinical 
condition, AEs, and blood tests for safety per the Study Schedule (Appendices 1 and 2). 
Safety laboratory assessments will be performed and reviewed by the investigator along 
with a copy of the patient’s diary. AEs and concomitant medications will be assessed 
over the phone or in person by the study team. If the patient is responding adequately to 
treatment (average diary score <0.5) or reduction in average diary score, the patient will 
continue receiving baricitinib therapy with follow-up appointments according to the 
Study Schedule (Appendices 1 and 2). If the patient is responding to treatment, but has 
not yet reached symptom control, dose escalation may be performed as discussed 

 
 
 
 
 
 
 
25
above and in Appendices 3 and 4. Once the patient has reached a stable dose of 
baricitinib, the same total dose may be administered as equal or unequal divided doses 
(administered up to 4 doses in a day [24 hours]).  
This section also applies to patients who continue treatment beyond Week 288. 
 
4.6 Immunosuppression monitoring during continuing treatment 
Recent data has clarified that subjects with AGS are at risk of hematologic 
disturbances, including neutropenia63. In addition, baricitinib is associated with 
neutropenia and leukopenia. However, AGS subjects treated with baricitinib typically 
have transient neutropenia and leukopenia that is not clinically significant63. As part of 
ongoing safety monitoring, we will continue to assess every 3 months the following 
laboratory studies: T cell subsets, immunoglobulins and CBC with differential. If these 
tests are all normal (CD4 >250 cell/l, ALC (Absolute lymphocyte count)>500/mm3, IgG 
>400mg/dL, ANC (Absolute Neutrophil Count) >1000/mm3), we will continue to follow 
immune function every 3 months. 
If individuals have abnormalities on ANY of the proposed testing (CD4 <250 cell/l, ALC 
<500/mm3, IgG <400mg/dL, OR ANC <1000/mm3), following management plans will be 
put in place and prophylaxis initiated (Appendix 10).  
a. Patients will be followed as per Appendix 10 with repeat CBC and immune 
phenotyping and drug tapering or discontinuation considered as per Appendix 14. 
b. For persistent abnormalities, patients will be clinically referred to an 
immunologist for clinical care with their local care team and will be asked to 
continue to clinically follow with this expert for immunosuppression as defined by 
CD4 <250 cell/l, ALC <500/mm3, IgG <400mg/dL, OR ANC <1000/mm3. 
c. Prophylactic approaches will also be put in place if patients on baricitinib have 
persistent abnormalities meeting specific criteria (Appendix 10). 
 
 
4.7 Concomitant Medication 
All concomitant medication taken during the study must be recorded on the eCRF. 
 
After starting baricitinib, if the patient, for any reason, requires treatment with another 
therapeutic agent that has been demonstrated to be effective for treatment of the study 
indication, tapering from protocol therapy occurs at start of or before the new agent is 
started. This is considered an event in the statistical analysis. Exceptions to this rule:  
1. Topical and inhaled corticosteroids are allowed.  
2. Pulses of corticosteroids (prednisone, hydrocortisone, dexamethasone, or 
methylprednisolone) at any dose for less than 7 days (consecutive or cumulative) in a 
28-day window are allowed.  
3. Daily hydrocortisone for adrenal insufficiency is allowed.  
4. Treatment for immune mediated hemolytic anemia or Immune mediated 
thrombocytopenia is allowed.  
5. If a patient is enrolled and is taking immune suppression at the time of initiation of 
baricitinib and stops this other immune suppressant for any reason, that immune 
suppressant can be restarted. 

 
 
 
 
 
 
 
26
 
Use of other concomitant medications will follow the parameters outlined in Appendix 
16. 
 
4.8 Dosing changes 
On occasion, if drug related adverse events are seen, changes or discontinuation of 
study medication will be considered. Because abrupt drug discontinuation may result in 
rebound inflammation, tapering of dosing to the next dosing increment (e.g. 2 mg three 
times a day to 2 mg twice a day – Appendix 14) may be considered in response to 
suspected drug related adverse events. Repeat laboratory testing will be performed 
after drug tapering and results will be discussed with the study team to assess that drug 
continuation at a lowered dose is in the best interest of the patient. 
 
4.9 Subject Completion/Withdrawal 
On occasion, the investigator may find it necessary to decrease (Appendix 14), 
temporarily interrupt or prematurely permanently discontinue investigational product 
administration following the occurrence of an AE or an abnormal laboratory finding. The 
investigator must notify the DSMB within 48 hours when decreasing, temporarily 
interrupting or prematurely permanently discontinuing therapy for an individual. If 
infection is the cause of the interruption, patients will receive treatment as clinically 
indicated for infections regardless of treatment decisions for baricitinib. 
Any patient who is permanently discontinued from investigational product for an 
abnormal laboratory result should have the abnormal laboratory result reported as an 
AE, or an SAE if the laboratory abnormality results in an outcome requiring the AE to be 
reported as an SAE. 
In addition, patients may be discontinued from the investigational product or from the 
study in the following circumstances: 
 
o The patient enrolls in any other clinical trial involving an investigational product or 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study. 
o An SAE or a clinically significant change in a laboratory value occurs that, in the 
opinion of the investigator, merits the investigational product being discontinued 
and appropriate measures being taken.  
o The investigator decides that the patient should be withdrawn from the study. 
o The parents, legal guardian, or patient requests to be withdrawn from the study. 
o Investigational product is no longer supplied. 
 
4.9.1 Early Termination Study Visit 
Subjects who withdraw from the study will have all procedures enumerated for the early 
termination visit as per the study schedule and timeline (Appendices 1 and 2) either in 
person or by telephone visit.  

 
 
 
 
 
 
 
27
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations: Performed as Part of Clinical Care 
5.1.1 Physical Examination 
One complete physical examination (excluding pelvic and rectal examinations) will be 
performed at screening. This examination will determine whether the patient meets the 
criteria required to participate in the study and will also serve as a monitor for 
preexisting conditions and as a baseline for TEAE assessment. Body weight and height 
will also be recorded. Additional limited physical examinations will also be performed 
during the study (Study Schedule in Appendices 1 and 2). Fundoscopy may be 
completed as part of the physical exam if complaints of headache are present or 
irritability worsens on medication, and ophthalmology may be consulted as clinically 
indicated. 
 
5.1.2 Vital Signs 
Vital signs (blood pressure and pulse) will be measured at times indicated in the Study 
Schedule (Appendices 1 and 2). Any clinically significant findings that result in a 
diagnosis should be captured on the eCRF and reported as an AE.  Additional 
measurements of vital signs may be performed at the discretion of the investigator. 
 
5.1.3 Cardiac monitoring 
Pulmonary hypertension (PH) is a rare but potentially fatal disorder characterized by 
severe vasculopathy and elevated pulmonary artery pressures leading to right-sided 
heart failure. Progressive PH has both genetic and inflammatory influences 28-34. In 
particular, type I interferons, as are overexpressed in AGS, have been established as 
risk factors for the development of PH 29,35-38. We have identified several individuals 
within our cohort with PH, as related to systemic interferon overexpression (paper 
submitted). Cardiac involvement will be quantified using clinical assessment and 
echocardiogram. As per World Health Organization (WHO) guidelines, PH will be 
defined as persistently elevated mean pulmonary arterial pressure of ≥25 mmHg and a 
pulmonary capillary wedge pressure of ≤15 mmHg for precapillary PH 64. In setting of 
contraindication to cardiac catheterization (e.g. critical illness), combined 
echocardiographic and clinical evidence of PH will be utilized 65. Individuals affected by 
AGS will have screening cardiac evaluations every other year, unless abnormalities are 
noted, on a clinical basis, with additional management as clinically indicated. If not 
previously performed on a clinical basis, this may be performed on a research basis. In 
the patients identified as being affected by PH, we will follow the relationship between 
PH, and the response to baricitinib. 
 
5.1.4 Electrocardiograms 
Twelve-lead ECGs will be obtained clinically during the screening process. A single 12-
lead ECG measurement will be performed at screening. Subsequently, ECGs will be 
obtained every other year as a part of clinical care to screen for pulmonary 
hypertension, in addition to echocardiograms every other year as discussed above. If 
not previously performed on a clinical basis, this may be performed on a research basis. 

 
 
 
 
 
 
 
28
 
5.1.5 Chest X-ray and tuberculosis screening 
During the screening process, we will review clinically obtained posterior-anterior view 
chest x-ray obtained within 6 months prior to the study. The chest x-ray will be reviewed 
by the investigator or his/her designee to exclude patients with active TB infection. In 
addition, patients will be tested at screening for evidence of active or latent TB as 
described above. 
 
5.1.6 Laboratory Evaluations 
Appendix 2 lists the schedule for sample collections in this study. Appendix 8 lists the 
specific tests that will be performed for this study. Some testing may occur outside of 
inperson study visits at CHOP and these will be considered as being performed as part 
of clinical care. 
In order to address constraints on blood volumes for laboratory tests in younger patients 
(<1 year), alternative methods of assessing baseline risk of hepatitis, HIV, or TB (e.g. 
testing of parent) may be considered, as well as limited PK studies. These will be 
considered as being performed as part of clinical care. 
 
5.1.7 Medical Record Review 
Include a listing of the variables that will be abstracted from the medical chart (paper or 
electronic). 
Date of birth 
Date of symptom onset 
Symptom complex at symptom onset 
Date of diagnosis 
Genotype 
MRI and CT findings 
Weight 
Height 
Head circumference 
Prior health events 
Prior and concomitant medications 
Level of baseline neurologic function (rolling, sitting, ambulation, speech etc). 
5.1.8 Pregnancy Testing 
A pregnancy test will be performed (if applicable).  
 
5.2 Screening and Monitoring Evaluations: Performed as a Part of Research 
5.2.1 Physical Examination 
One complete physical examination (excluding pelvic and rectal examinations) will be 
performed at screening. This examination will determine whether the patient meets the 
criteria required to participate in the study and will also serve as a monitor for 
preexisting conditions and as a baseline for TEAE assessment. Body weight and height 
will also be recorded. Additional limited physical examinations will also be performed 

 
 
 
 
 
 
 
29
during the study (Study Schedule in Appendices 1 and 2). Fundoscopy may be 
completed as part of the physical exam if complaints of headache are present or 
irritability worsens on medication, and ophthalmology may be consulted as clinically 
indicated. 
 
5.2.2 Vital Signs 
Vital signs (blood pressure and pulse) will be measured at times indicated in the Study 
Schedule (Appendices 1 and 2). Any clinically significant findings that result in a 
diagnosis should be captured on the eCRF and reported as an AE.  Additional 
measurements of vital signs may be performed at the discretion of the investigator. 
 
5.2.3 Symptom Diaries 
Symptom diaries are to be completed for at least two years from treatment initiation. 
Refer to Appendices 6 and 7 for symptom diaries. 
 
5.2.4 AGS Scale 
Refer to Appendix 5 for AGS Scale, which will be applied at baseline, 3 months, 6 
months, 9 months,12 months and every subsequent study visit through neurologic exam 
and conversation with parents. 
 
5.2.5 GMFM-88 
Individuals affected by AGS can have a range of motoric disability, secondary to direct 
muscle inflammation (myositis) as well as from injury to the central nervous system. The 
GMFM-88, administered by trained physiotherapists, covers 5 distinct categories: lying 
and rolling, sitting, crawling and kneeling, standing, and walking and running. 
Preliminary data demonstrates the feasibility of GMFM-88 in individuals affected by 
AGS (Figure 7). We will continue these serial assessments and compare the GMFM-88 
scores to the clinical diaries, skin manifestations, and IFN signature scores, as 
described elsewhere. 
Composite scores for the GMFM-88 will be calculated 25,46,66 and compared to 
normative data. Additionally, domain and subdomain scores will be recorded as raw and 
standardized scores. Functional measures developed for typically developing or mildly 
affected children (cerebral palsy) have not been validated in severe disorders such as 
AGS. However, our preliminary data suggests that these measures are reliable 
measures in AGS subjects. 
 
The GMFM-88 may be performed remotely, via video assessment. The remote 
assessments will be performed by trained therapists that will administer the assessment 
and score the performance live, having the patients’ parents assisting their children if 
needed according to a published, validated approach67.   
The families will be provided with information prior to the research encounter regarding 
the necessary environment and technology needed for home evaluations, as included in 
the following table:  
 

 
 
 
 
 
 
 
30
Small bench smaller than 3’ (feet touch floor when sitting)    
Large bench to stand and cruise           
12”-24” stick     
Large object to carry with two hands (soccer ball or similar)  
5 steps/rail         
2 straight parallel lines 20’ x ¾’ and 20’ x 8”              
24” circle  
  
Sessions will be conducted over a secure video conferencing platform (e.g.: Cisco 
WebEx/BlueJeans/myCHOP). Existing home equipment, including typical home 
furniture, will be selected to be as close as possible to the standard equipment and for 
subsequent evaluations and logged for consistency, in accordance with the GMFM-88 
manual. All 88 items will be administered during the virtual encounter. Session will be 
recorded with a fixed camera angle. 
 
5.2.6 AGS Development  
In addition to formal measurement of motor function through the AGS scale and the 
GMFM-88, we will also employ descriptive approaches to assess typical developmental 
milestones. Progressive childhood diseases, such as AGS, offer unique complications 
in that they require the assessment of children with potentially worsening skills 
superimposed on an evolving panel of predicted developmental milestones. This scale 
allows for assessment of skills (smiling, head control, rolling) as compared to the 
average (P50) child affected by AGS, as opposed to age-matched controls (Figure 2). 
We will assess the longitudinal benefit of baricitinib on the rate of acquisition of skills in 
the domains of motor, speech and manual abilities. These scales can be applied using 
historical data acquired during clinical encounters with validated functional tools 
including the gross motor function classification system (GMFCS), manual ability 
classification system (MACS), communication function classification system (CFCS), 
and the Eating and Drinking Ability Classification system (EDACS) 68. 
 
5.2.7 Skin Inflammation 
 As one of the most clinically measurable manifestations of AGS is the dermatologic 
involvement, we have initiated a project to define and quantitate the skin manifestations 
found in patients with AGS. Aside from neurologic injury, skin manifestations are one of 
the most common manifestations of AGS, occurring in over 30% of affected individuals2. 
As hypothesized, in our preliminarily results, the skin manifestations in AGS have been 
robustly responsive to baricitinib therapy (Figure 3). 
Additional investigations will utilize the assessment tool CLASI (Cutaneous Lupus 
Erythematosus Disease Area and Severity Index) before and after treatment with 
JAK1/2 inhibitor. The dermatologic findings will be correlated with measures of 
neurologic function and the clinical diary as described above. The skin ulcerations and 
chilblains found in individuals affected by AGS are hypothesized to be secondary to an 
underlying vasculopathy 57-59. All AGS subjects will undergo a standardized 
dermatologic evaluation as well as the CLASI, a validated measurement instrument for 
skin disease (Cutaneous Lupus Erythematosus Disease Area and Severity Index)60. 

 
 
 
 
 
 
 
31
This scale has established content validity and reliability 60,69 and was developed in 
collaboration with our collaborator Dr. Treat who is experienced in its application and 
analysis. It has since been used extensively in clinical trials in SLE 39,40,70-73, and 
appears responsive to treatment. These evaluations will be performed by 2 independent 
clinicians for each assessment. Any patient identified as having skin abnormalities 
(expected approximately 30% 3) will be referred for a full dermatologic evaluation.  
 
5.2.8 Cardiac monitoring 
Pulmonary hypertension (PH) is a rare but potentially fatal disorder characterized by 
severe vasculopathy and elevated pulmonary artery pressures leading to right-sided 
heart failure. Progressive PH has both genetic and inflammatory influences 28-34. In 
particular, type I interferons, as are overexpressed in AGS, have been established as 
risk factors for the development of PH 29,35-38. We have identified several individuals 
within our cohort with PH, as related to systemic interferon overexpression (paper 
submitted). Cardiac involvement will be quantified using clinical assessment and 
echocardiogram. As per World Health Organization (WHO) guidelines, PH will be 
defined as persistently elevated mean pulmonary arterial pressure of ≥25 mmHg and a 
pulmonary capillary wedge pressure of ≤15 mmHg for precapillary PH 64. In setting of 
contraindication to cardiac catheterization (e.g. critical illness), combined 
echocardiographic and clinical evidence of PH will be utilized 65. Individuals affected by 
AGS will have screening cardiac evaluations every other year. If not previously 
performed on a clinical basis, this may be performed on a research basis. In the 
patients identified as being affected by PH, we will follow the relationship between PH, 
and the response to baricitinib. 
 
5.2.9 Electrocardiograms 
Twelve-lead ECGs will be obtained clinically during the screening process. A single 12-
lead ECG measurement will be performed at screening. Subsequently, ECGs will be 
obtained every other year as a part of clinical care to screen for pulmonary 
hypertension, in addition to echocardiograms every other year as discussed above. If 
not previously performed on a clinical basis, this may be performed on a research basis. 
 
5.2.10 Chest X-ray and tuberculosis screening 
During the screening process, if no chest x-ray was done clinically within 6 months prior 
to the study, chest x-ray will be done as part of the research study. The chest x-ray will 
be reviewed by the investigator or his/her designee to exclude patients with active TB 
infection. In addition, patients will be tested at screening for evidence of active or latent 
TB as described above. If this has not been done clinically, in the context of standard of 
care, this will be done on a research basis. 
 
5.2.11  Bone growth monitoring 
Animal studies have elicited concerns about bone growth in juvenile animals. Height 
and weight will be monitored every 6 months. If patients are <1%, they will be referred 
to their local pediatric team for clinical management. Bone growth monitoring will be 
performed to include hand/wrist/fingers X-rays at baseline, 6 months, 12 months and 

 
 
 
 
 
 
 
32
then every 12 months as long as there are no radiographic concerns. The hand is 
placed on or up against a hard plate while a camera-like machine is placed opposite of 
the plate. This machine sends a very small burst of radiation which passes through the 
hand and creates images on the recording plate. IGF-1 will be completed yearly with 
safety labs. This will be completed on a research basis. With IGF-1 abnormalities, or 
radiographic concerns for accelerated bone growth, we will refer to bone health team for 
clinical monitoring. 
Hand/wrist/fingers X-rays and IGF-1 testing will not be completed after a bone age 
demonstrating complete growth. 
 
5.2.12 Laboratory Evaluations 
Appendix 2 lists the schedule for sample collections in this study. Appendix 8 lists the 
specific tests that will be performed for this study. The blood volume frequencies will not 
exceed the volumes permitted by the NIH (no more than 5 mL/kg may be drawn for 
research purposes in a single day and no more than 9.5 mL/kg may be drawn over any 
eight-week period for children, and no more than the lesser of 10.5 mL/kg or 550 mL 
may be drawn for research purposes over an 8-week period for adults). 
In order to address constraints on blood volumes for laboratory tests in younger patients 
(<1 year), alternative methods of assessing baseline risk of hepatitis, HIV, or TB (e.g. 
testing of parent) may be considered, as well as limited PK studies. If not previously 
performed on a clinical basis, this may be performed on a research basis. 
 
5.2.12.1 
Samples for Standard Laboratory Testing 
Blood and urine samples will be collected at the times specified in the Study Schedule 
(Appendices 1 and 2). Standard laboratory tests, including chemistry, hematology, and 
urinalysis panels, will be performed. Every effort should be made to obtain all laboratory 
tests listed in Appendix 8. Missing laboratory testing will be reported in aggregate to the 
IRB during continuing reviews. The blood volume frequencies will not exceed the 
volumes permitted by the NIH. 
Standard age based pediatric norms will be used to assess out of range values for 
laboratory testing.  
Additional blood samples may be drawn if needed for safety purposes and/or if 
warranted. Investigators must document their review of each laboratory safety report. 
 
Liver-Function Monitoring 
Liver-function monitoring will occur frequently throughout the study. It should be noted 
that approximately one-third of individuals with AGS have elevations of AST and ALT 
that are consistent with hepatitis at baseline (AST and ALT fold increase of 3 times and 
GGT fold increase of 2.5 times from upper limit of normal). Thus, use of standard 
metrics such as the Recommended Hepatic Evaluation Guidance Document are difficult 
to apply in this population. If elevations in ALT/AST or total bilirubin occur from the 
patient’s baseline, the patient should be closely observed in consultation with study staff 
with expertise in hepatology and the Management of Liver Enzyme Laboratory Values 
(Appendix 9). 
 
 

 
 
 
 
 
 
 
33
Other safety monitoring 
Other clinical safety testing, including CBC, renal function and infectious testing will be 
discussed with study team and the clinical care providers. 
 
5.2.13 Safety Evaluation 
Subject safety will be monitored by adverse events, vital signs, physical examinations, 
and laboratory data (Appendices 2 and 8). Interruption of intervention will be considered 
in consultation with the study team and the clinical care providers (Appendices 9, 10, 
11, 12). 
 
5.2.14 Administration of Study Drug 
Study drug will be administered as described in Section 4, and in Appendices 3 and 4, 
of the protocol.  
 
5.2.15 Medical Record Review 
Include a listing of the variables that will be abstracted from the medical chart (paper or 
electronic). 
Date of birth 
Date of symptom onset 
Symptom complex at symptom onset 
Date of diagnosis 
Genotype 
MRI and CT findings 
Weight 
Height 
Head circumference 
Prior health events 
Prior and concomitant medications 
Level of baseline neurologic function (rolling, sitting, ambulation, speech etc). 
5.2.16 Pregnancy Testing 
A pregnancy test will be performed (if applicable).  
 
5.2.17 Pharmacokinetic Evaluation 
Samples for Drug Concentration Measurements Pharmacokinetics 
Venous blood samples for the measurement of baricitinib concentrations will be 
collected from all patients enrolled in the study. Samples will be collected after 
beginning baricitinib therapy and at each dose increase at the time points shown in 
the Study timeline and may be collected at each study visit with blood sampling for 
safety monitoring. In these cases, PK sampling will occur at least 72 hours after 
dosing changes or at the next visit. 
PK testing may include a single measurement at 1.5 hours, or a full PK series at 
baseline, 1.0 hours, 1.5 hours and 4 hours post dose, and may include several doses 
during the day (eg morning and afternoon dose). For PK series, an IV will be placed. 

 
 
 
 
 
 
 
34
For single PKs, these will be drawn with the safety laboratory monitoring. PK samples 
may be banked for later analysis. 
If a patient has an adequate response to treatment at a lower dose than the maximum 
dose, but becomes unresponsive at a later time, the schedule of dose increases and PK 
sampling can be resumed.  If a patient’s daily dose is divided into multiple doses, an 
additional PK sample may be collected pre-dose for each additional dose. For all PK 
samples taken, the actual date and exact timing (24-hour clock) of PK sample collection 
and the date and time of the last 2 doses prior to the PK sample should be recorded. 
Plasma samples will be kept frozen at approximately –20º C to –80º C until the time of 
the assay. The assay may be performed at a later time. Samples will be kept in storage 
at a laboratory facility designated by the Sponsor. If the blood volumes required for PK 
sampling exceed established local guidelines for phlebotomy, then the PK sample 
collection may be modified. 
 
5.2.18 IFN Signaling Gene Score 
IFN scores are based on mRNA expression of IFN signaling genes (ISG) and represent 
a surrogate marker for autoinflammation in a variety of disorders 39-41. IFN scores based 
on mRNA expression of ISGs have been used to assign a severity score of 
autoinflammation in a variety of disorders, including AGS 4 and systemic lupus 
erythematous 39,40. We will measure ISG in individuals affected by AGS as per 
established protocol 4,42,43. ISG scores will be calculated for all AGS affected individuals 
in the MDBP registry with available blood samples (180 AGS samples and 104 control 
samples) as per established methodology 4,42-44. In brief, copy number of mRNA 
transcripts of the six type I IFN-inducible genes (IFI27, IFI44L, IFIT1, ISG15, RSAD2, 
and SIGLEC1) 4 and four housekeeping genes (ALAS1, HPRT1, TBP, and TUBB) are 
quantified using Nanostring nCounterTM Digital Analyzer. The raw copy number of 
mRNA transcripts of each type I IFN-inducible gene is standardized (stdGene) using the 
geometric mean of the four housekeeping genes for each individual. The six-gene IFN 
signature in each individual is calculated using the median of the Z scores. The IFN 
signature is considered positive (IFN high) if the value is ≥1.96 (>98centile) (one tail 
analysis). This test is a research test performed in a non CLIA approved laboratory, and 
will not be used to make clinical decisions around enrollment or patient management. 
 
5.2.19 Leftover Samples for Future Research 
Samples obtained during the course of this research project that represent leftover 
biological samples, will be stored by the sponsor and analyzed in the future, based on 
scientific questions that may arise during the course of the project. 
 
 

 
 
 
 
 
 
 
35
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary endpoint will be the change in the AGS scale from baseline to 52 weeks. 
 
6.2 Secondary Endpoints 
Secondary endpoints will include the following: 
• Improvement of the AGS scale from Screening to Treatment over time. 
• Improvement of the GMFM-88 between Screening and Treatment over time. 
• The change in Interferon Signaling gene score between Screening and 
Treatment over time. 
• The change in skin symptoms between Screening and Treatment over time using 
the CLASI. 
• Safety and tolerability of DRUG based on Adverse Events (including laboratory 
abnormalities).  
• Change in AGS disease severity score (daily diary) between Screening and two 
years of treatment. 
 
6.3 Statistical Methods 
6.3.1 Baseline Data and Descriptive Analysis 
Baseline and demographic characteristics will be summarized overall by standard 
descriptive summaries (e.g. means and standard deviations for continuous variables 
such as age and percentages for categorical variables such as gender). 
In addition, demographic characteristics and clinical variables that are evaluated at the 
first encounter will be compared between subjects who are never treated, versus those 
who are eventually treated. Patients are not randomized to receive treatment (or not), 
so it is important to identify variables that are associated with an increased (or 
decreased) likelihood of receiving treatment. Chi-square tests will be used to compare 
categorical variables between groups. T-tests or tests of medians (for skewed variables) 
will be used to compare continuous variables between groups. Overlaid histograms will 
also be used to evaluate the distribution of continuous baseline variables between 
patients who were never treated, versus those who were eventually treated.  
In addition, Kaplan-Meier analysis with the log rank test will be used to compare the 
distribution of time to treatment between levels of categorical variables (e.g. group 
genotype) measured at baseline. In our preliminary analysis, we did not identify 
meaningful differences between patients who were never treated, versus those who 
were eventually treated. 
We will conduct descriptive statistical analysis using inferential and graphical secondary 
data analytic techniques. The primary and secondary assessments will first be 
summarized by time of measurement. In addition, individual “spaghetti” plots will be 
generated for each assessment. Changes in primary and secondary outcomes from 
baseline (with 95% confidence intervals [CI]) will be calculated at specified time points, 
e.g. between baseline and 52 weeks. In addition, overall changes (final minus baseline) 
(with 95% CI) will be computed for primary and secondary outcomes. In addition to 
means (with 95% CI) we will also calculate median changes (with 25th to 75th 

 
 
 
 
 
 
 
36
percentiles). Analyses will be conducted in Stata 18.0, with a p-value < 0.05 as the 
criterion for statistical significance. 
 
6.3.2 Primary Outcome Analysis 
As is often the case in a study of a rare disease, we face a number of challenges in our 
analysis. The number of available patients with AGS is limited, so that our sample size 
is small. This protocol grew out of a compassionate use trial, so that randomization 
could not be employed to assign patients to receive treatment (or not). The temporal 
spacing of measurements differs between treated patients versus historical controls. As 
a result of these features, there are limitations to many of the standard statistical 
approaches. Our approach will therefore be to apply a recommended approach for 
efficacy, but to also apply several sensitivity analyses. Our goal will be to demonstrate 
efficacy for several statistical approaches, as we achieved in our analysis of preliminary 
data. 
 
Our efficacy analysis for our primary outcome will apply the method described in 
Section 15.4 of Fitzmaurice, Laird, & Ware74 that decomposes longitudinal effects of 
treatment versus cross-sectional effects due to participants starting treatment at 
different ages. We will first create a time for each patient that is negative prior to 
treatment and is positive after treatment. We will then fit a GEE model that includes time 
within patients, an indicator variable for treatment and a time by treatment interaction 
term. If the interaction term is significant, this will indicate that the change over time in 
AGS score (slope) is different after treatment, versus before. If the interaction term is 
not significant, it will be removed and the model will be fitted with time and the indicator 
variable for (post) treatment. If the indicator variable differs significantly from zero, this 
will indicate that the AGS score is higher on average, post-treatment. To compare 
values at baseline and 52 weeks post baseline, different parameterizations of time 
(continuous versus indicator variables at different visits) will be considered and analyses 
will also be performed on data restricted to values measured at baseline and 52 weeks 
post baseline.  This approach will first be applied to patients who are eventually treated, 
to compare their AGS scores pre versus post-treatment.  
 
6.3.3 Secondary Outcome Analysis 
 
6.3.3.1 Longitudinal analysis of the AGS scale 
In secondary analysis, we will include historical controls in the GEE models described in 
section 6.3.2; the “age at treatment” (time zero) for controls will be their age at their final 
encounter. The GEE models will also adjust for confounders (e.g. age of the subject, 
length of disease, and genotype75) especially variables that were identified as being 
related to receiving treatment (see Section 6.3.1). We will fit several working correlation 
structures to model the association between the repeated measurements on each 
patient, and will use goodness of fit criteria for GEE to choose between the structures. 
Goodness of fit criteria will also be used to compare fit of models (e.g. for models that 
include time as a continuous variable versus a series of indicator variables for visit). 

 
 
 
 
 
 
 
37
In addition to GEE, we will fit quasi-least squares (QLS) regression models.76 QLS is a 
computational approach for estimation of the correlation parameters in the framework of 
GEE that can be applied should GEE fail to converge, or to fit correlation structures that 
are not available in the framework of GEE. For example, the Markov correlation 
structure that is plausible for unequally spaced data is not available in the xtgee 
command for implemention of GEE in Stata.   
 
In addition to the GEE analysis that includes historical controls, we will implement 
several sensitivity analyses that are described in the Table below. These methods were 
successfully implemented in analysis of our preliminary data.  
 
Table 2. Statistical Approaches 
Question to be Evaluated in 
Sensitivity Analysis 
Statistical Approach 
For each patient who was 
eventually treated, if we obtain 
their average of their AGS 
scale values prior to treatment 
(pre-treatment average) and 
the average of their AGS scale 
values after treatment (post-
treatment average), are the 
post-treatment averages higher 
than the pre-treatment 
averages? 
Compute the average of the within subject changes (post-treatment 
average minus pre-treatment average) with 95% CI; apply the 
paired t-test to compare the mean of pre-treatment to the mean of 
post-treatment averages within patients. 
Is the average AGS scale value 
higher after treatment than 
before treatment, when we 
modify the previous analysis to 
include patients who were 
never treated, by calculating 
their pre-treatment average 
AGS scale as the average of all 
of their AGS scale values? 
GEE analysis in which patients who were treated contribute two 
measurements (pre-treatment average and post-treatment 
average), while patients who were never treated contribute one 
measurement (“pre-treatment” average of AGS scale). The GEE 
model will include an indicator variable for post-treatment and use 
an exchangeable correlation structure to account for the intra-
subject correlation of measurements on each patient. 
 
 
Does the AGS scale at 
screening differ from the final 
value within patients? 
Paired t-tests or non parametrics Wilcoxon signed-rank test will be 
applied as appropriate to compare the screening and final values 
within patients. 
 
 
6.3.3.2 Analysis of the GMFM-88 
In addition, we will perform a secondary analysis of the GMFM-88 based on the cohort 
designation in AGS subjects based on their baseline AGS scale. As described earlier, 
the AGS scale is simple enough to be able to be applied retrospectively, based on 
clinical notes; this allowed us to develop a historical control cohort for comparison. 
Based on our pilot data, we have defined three cohorts for this study (Table 3) 
according to baseline neurologic function as measured by the AGS scale. The more 
severely affected individuals, due to floor effect, will use the AGS scale as a primary 

 
 
 
 
 
 
 
38
outcome measure. Individuals with baseline AGS scales of >9 have measurable 
function on the GMFM-88 and other functional assessments and this can be applied to 
this population.   
 
Changes in GMFM-88 will first be compared between AGS cohorts descriptively, 
including graphical displays (e.g. overlaid lowess curves for each outcome versus 
treatment day, by cohort). GEE models will be fitted that model change in outcome over 
time; these models will include indicator variables for cohorts B and C (with cohort A as 
reference) and time by cohort interaction terms. Different parameterizations of time will 
be considered and the fit of models will be compared using goodness of fit criteria for 
GEE. 
 
Table 3. Cohort designation in AGS subjects based on baseline AGS scale.  
 
AGS cohort 
A. AGS scale 0-3 
B. AGS scale 4-8 
C. AGS scale 9-11 
 
 
6.3.3.3 Analysis of the ISG scores 
Initial analyses will be descriptive (see section 6.3.1). GEE and QLS models will also be 
fitted, using the same approaches that were described for AGS scale (see sections 
6.3.2 and 6.3.3.1). In addition, quantile regression may be applied to evaluate change in 
median ISG. 
 
 
6.3.3.4 Analysis of symptoms diaries scores 
Initial analyses will be descriptive (see section 6.3.1). GEE and QLS models will be 
fitted for evaluation of symptoms diaries scores, using the same approaches that were 
described for AGS scale (see sections 6.3.2 and 6.3.3.1) but potentially with some 
adjustment for differential timing of measurement.  
 
 
6.3.3.5 Correlation of within participant changes in primary and secondary 
outcomes 
In addition to individual analysis of each primary and secondary outcome, we will also 
evaluate the correlation of intra-subject changes in outcomes with Pearson or 
Spearman correlations, as appropriate. We hypothesize that as the inflammation is 
lowered (as shown by the IFN score decreasing), the clinical measures of inflammation 
will improve, as measured by the primary (AGS development score) and secondary 
outcomes (clinical diaries, GMFM-88). 
 
 

 
 
 
 
 
 
 
39
6.3.3.6 Special considerations 
As described earlier, subjects enrolled in the Compassionate Use Treatment Protocol 
I4V-MC-JAGA (JAGA Compassionate Use study, CHOP IRB Study #13205) for whom 
commercial supply is not available, will be reconsented to the investigator-initiated JAK 
inhibitor treatment in AGS study. Data collected as part of their participation in IRB 
#13205 will be included as part of their longitudinal analysis, including baseline studies. 
Additionally, subjects who did not transition to this investigator-initiated study because 
they obtained commercial supply or discontinued participation in I4V-MC-JAGA will be 
consented via a separate consent form to permit inclusion of their data. For subjects 
who are considered lost to follow-up (unable to be reached after multiple attempts), a 
waiver of consent and HIPAA authorization will apply for inclusion of their data. This 
comprehensive approach is important to overall understanding of efficacy and safety in 
this ultra rare disease. 
Because the JAGA Compassionate Use study protocol and this protocol are carefully 
aligned, we do not anticipate that any observed within patient changes in study 
outcomes will be due to differences in procedures between the two studies. However, 
we will perform sensitivity analyses, to determine if changes in outcomes with treatment 
differ between the two groups (data from patients enrolled only in the JAGA 
Compassionate Use study, data from patients who have been enrolled in both the JAGA 
study and the investigator-initiated JAK inhibitor in AGS study versus data from patients 
who are solely enrolled in the JAK inhibitor in AGS study). To the GEE model that 
includes time within patients, an indicator variable for treatment and a time by treatment 
interaction term, we will add an indicator variable for JAK inhibitor in AGS study and a 
three way interaction term that is constructed as the product of time and treatment and 
the study indicator. If the three way interaction term is significant, this will indicate that 
the impact of treatment (change over time with treatment) differs significantly between 
groups.  
 
6.3.4 Pharmacokinetic Analysis 
Pharmacokinetic sampling may be performed according to the study schedule and 
analysis may be performed at a later time. 
 
6.3.5 Safety Analysis 
All subjects entered into the study at Visit 1 will be included in the safety analysis. The 
frequencies of AEs by type, body system, severity and relationship to study drug will be 
summarized. SAEs (if any) will be described in detail. AE incidence will be summarized 
along with the corresponding exact binomial 95% two-sided confidence intervals. 
 
6.4 Sample Size and Power 
Sample size calculations were performed using PASS 16 sample size software and 
were based on preliminary data in 35 patients with available data on the AGS scale.  
 
Analysis of the primary outcome, safety data including laboratory studies and adverse 
events, will be descriptive and include all individuals, available studies and AEs. Power 

 
 
 
 
 
 
 
40
analysis is not possible for these analyses, since adverse events may be rare, even in 
the AGS population, and statistical comparisons may not be feasible.  
 
We anticipate that we will have an evaluable sample size of ~45 treated patients. For 
the analysis of secondary outcomes, in our preliminary analysis when we compared the 
average of AGS scales prior to treatment (pre-treatment average) to the average of the 
AGS scale after treatment (post-treatment average), we observed that the average of 
within subject changes (post-treatment average minus pre-treatment average) was 0.80 
(95% CI = 0.45, 1.16) and that the standard deviation of changes was 1.04. This 
corresponds to an effect-size of 0.80/1.04 = 0.77. From PASS 16, a sample size of 30 
data pairs achieves 98.3% power to reject the null hypothesis of zero effect size when 
the population effect size is 0.77 and the significance level (alpha) is 0.050 using a two-
sided paired t-test. Should the effect-size be smaller than we observed in our 
preliminary data, we will have 80% power to detect an effect size of 0.53, which would 
correspond to an average of within subject changes of 0.55, if the SD of changes is 
1.04. We will therefore have sufficient power to detect differences that are similar to 
those observed in preliminary data. For the more complex analyses that are proposed 
for the larger data set that contains the historical controls (>50), our power will be even 
greater.  
 
Drop-Out: Overall, this clinical study may enroll up to 55 patients. However, power 
analysis suggest that an enrollment number of up to approximately 30 is required to 
obtain results for efficacy that are clinically meaningful, and accounting for those 
subjects who are found to be ineligible at screening, subjects withdrawn from 
participation for various reasons and those who are enrolled to this study who are not 
initially eligible at screening. In addition, some participants may be lost to follow up, or 
may not survive until one-year post-baseline, when the primary efficacy analysis will be 
conducted. Thus, we expect to be able to perform the necessary analysis even if there 
is significant drop out. 
We will evaluate the reasons for drop-out carefully, especially with respect to the 
missing at random assumption that is required for GEE/QLS regression. As described 
above, a sample size of 30 patients will be adequate for analysis of our primary 
outcome. The goal of the secondary analyses will be primarily to inform the generation 
of hypotheses for future studies in this population.  
The analysis of data obtained from this group of initially ineligible, but prospectively 
approved subjects entered to the study, will be assessed independently of the main 
group of subjects who meet all eligibility criteria. The statistical analysis within this group 
will depend on the total number of subjects in the group, as well as the degree of clinical 
heterogeneity of these patients. If the sample size is large enough we will attempt to 
replicate the analyses that are performed for the eligible participants in this group.    
 

 
 
 
 
 
 
 
41
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) 
7.1 Description 
7.1.1 Packaging 
Baricitinib will be dispensed by the investigational pharmacy in labeled containers. 
 
7.1.2 Labeling 
Individual labeling for drug packaging will be provided by the investigational pharmacy. 
 
7.1.3 Dosing 
Baricitinib can be taken orally or administered via G-tube. Baricitinib should be handled 
with gloves by caretakers. Dosing will be performed according to dosing tables 
(Appendices 3 and 4). 
 
7.1.4 Treatment Compliance and Adherence 
Patient compliance with investigational product will be assessed at each visit. 
Compliance will be assessed by counting returned tablets. Patients found to be 
noncompliant per investigator judgment should be assessed to determine the reason for 
noncompliance and educated and/or managed as deemed appropriate by the 
investigator to improve compliance. 
 
7.1.5 Drug Accountability 
Adequate records of study drug receipt and disposition will be maintained by the CHOP 
Pharmacy. Records of receipts, investigational drug orders, dispensing records, and 
disposition forms will be examined during the course of the study.  The purpose of these 
records is to ensure regulatory authorities that the investigational new drug will not be 
distributed to any person who is not a study subject under the terms and conditions set 
forth in this protocol.  The study medication is to be prescribed by the Investigator or 
designee and may not be used for any purpose other than that described in this 
protocol.  

 
 
 
 
 
 
 
42
8 
SAFETY MANAGEMENT 
The study protocol will be submitted to the FDA and will be reviewed by the study 
DSMB and the Medical Monitor. Participant enrollment may only begin after final IRB 
approval and FDA authorization to proceed.  
 
8.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
 
8.2 Adverse Event Reporting 
Unanticipated problems related to the research involving risks to subjects or others that 
occur during the course of this study (including SAEs) will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to 
Subjects. AEs that are not serious but that are notable and could involve risks to 
subjects will be summarized in narrative or other format and submitted to the IRB at the 
time of continuing review.  
 
8.3 Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received an 
intervention (drug, biologic, or other intervention).  The occurrence does not necessarily 
have to have a causal relationship with the treatment.  An AE can therefore be any 
unfavorable or unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case report 
form with a full description including the nature, date of onset, determination of non-
serious versus serious, intensity (mild, moderate, severe), duration, causality, and 
outcome of the event. 
As defined in title 21 of the Code of Federal Regulations Part 312, an adverse event 
(AE) is “any untoward medical occurrence associated with the use of a drug, whether or 
not considered drug related”. All adverse events will be classified using the current 
version of Common Terminology Criteria for Adverse Events (CTCAE), developed and 
maintained by CTEP at the National Cancer Institute.  
A suspected adverse reaction is any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. "reasonable possibility" means that 
there is evidence, such as a temporal relationship, to suggest a causal relationship 
between administration of drug and the adverse events. It is less certain about causality 
than adverse reaction. 
 
8.4 Definition of a Serious Adverse Event (SAE) 
Title 21 of the CFR also provides a definition for serious adverse events (SAEs), 
described as those events that result in death; or are life-threatening; or require 
prolonged inpatient hospitalization or prolongation of existing hospitalization; or create 
persistent or significant disability/incapacity, or a congenital anomaly/birth defects.  
However, application of this definition is difficult in subjects who, as a result of their 

 
 
 
 
 
 
 
43
underlying congenital disorder, present with life-threatening illness. Therefore, for this 
study, we modify the standard definition, and define serious adverse events as those 
events that: 
• Result in death. 
• Are life-threatening, that is, places the patient at immediate risk of death 
from the event as it occurred.  
• Require hospitalization.  
• Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious adverse drug events 
when, based upon appropriate medical judgment, they may jeopardize the 
patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 
 
Previously planned (prior to signing the ICF) surgeries should not be reported as SAEs 
unless the underlying medical condition has worsened during the course of the study. 
Elective admissions for surgeries or interventions, such as orthopedic surgeries, that 
are expected complications of AGS, will not be considered SAEs. Admissions for 
expected complications of AGS, including seizures, changes in neurologic function, 
interventions for tone management, interventions for feeding failure, will not be 
considered SAEs. All admissions associated with infection or hematologic disturbances 
will be reported as SAEs.  
 
8.4.1 Expected and Unexpected Adverse Events 
An unexpected adverse event or reaction is defined as any adverse experience, the 
specificity or severity of which is not consistent with the risks of information described in 
the protocol. Expected adverse events are those that are identified in the research 
protocol as having been previously associated with or having the potential to arise as a 
consequence of participation in the study or are part of the clinical spectrum of the 
underlying disorder. Common acute and chronic complications of AGS include but are 
not limited to: 
• 
Seizures 
• 
Intermittent encephalopathy 
• 
Progressive decline in neurologic function 
• 
Skin rashes (such as chilblains) including panniculitis and secondary infections 
and amputations 
• 
Large vessel central nervous system vasculitis 
• 
Lupus like renal dysfunction 
• 
Autoimmune hepatitis and elevation of liver enzymes and liver function tests 
• 
Pulmonary hypertension  
• 
Cardiomyopathy 
• 
Myopathy 
• 
Glaucoma 
• 
Gastrointestinal disease with bowel inflammation 
• 
Urinary tract infection 
• 
Hip dislocation or scoliosis 

 
 
 
 
 
 
 
44
• 
Chronic lung disease 
• 
Spasticity and dystonia 
• 
Feeding difficulties 
• 
Thrombocytopenia 
• 
Anemia 
• 
Hypothyroidism 
• 
Gastroesophageal reflux 
 
8.4.2 Relationship of SAE to study drug or other intervention 
Relationship of study drug to the adverse event or suspected adverse reaction is 
defined as follows: 
 
• 
Unrelated:  Adverse event is clearly due to extraneous causes (e.g., underlying 
disease) 
 
• 
Unlikely related (must have 2 of the below):  
- Does not have temporal relationship to drug administration 
- Could readily have occurred due to subject's clinical state 
- Could have been due to environment or other interventions 
- Does not follow known pattern of response to drugs 
- Does not reappear or worsen with reintroduction of drug 
 
• 
Possibly related (must have 2 of below):  
- Drug administration and the occurrence of the AE are reasonably related 
in time  
- Could not readily have occurred due to subject's clinical state 
- Could not readily be due to environment or other interventions 
- Follows a known pattern of response to drug 
 
• 
Probably related (must have 3 of the below):  
- Drug administration and the occurrence of the AE are reasonably related 
in time  
- Could not readily have occurred due to subject's clinical state 
- Could not readily be due to environment or other interventions 
- Follows a known pattern of response to drug 
 
• 
Definitely related (must have all 4 of the below):  
- Drug administration and the occurrence of the AE are reasonably related 
in time  
- Could not readily have occurred due to subject's clinical state 
- Could not readily be due to environment or other interventions 
- Follows a known pattern of response to drug 
 

 
 
 
 
 
 
 
45
8.5 IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The study coordinator is responsible for collecting and recording all clinical and 
laboratory data. Adverse events will be collected on subjects at all follow ups, as well as 
by phone or e-mail communication with parents 4 weeks following initiation of study 
agent. The reporting period for new AEs is the period from the start of study drug 
administration until one month after cessation. Follow-up reports on AEs should 
continue up to 30 days after the administration of drug if the AE did not resolve. 
For each AE, the site investigator will assess severity, and whether the event meets the 
definition of a serious adverse event and will report whether baricitinib treatment was 
interrupted or stopped, as well as the outcome of the AE. If the event is an SAE, both 
the site PI and the Medical Monitor will assess the relationship to drug.  
If a non-serious adverse event is unresolved at the time of assessment, the site 
investigator will make a clinical assessment as to whether continued follow-up of the AE 
is warranted, and the results of this assessment must be documented. If a non-serious 
adverse event is unresolved at the time of discharge from the study, the Principal 
Investigator and the Medical Monitor will make a joint clinical assessment as to whether 
continued follow-up of the AE is warranted. Resolution is defined as the return to 
baseline status or stabilization of the condition with the expectation that it will remain 
chronic.  
The PI will prepare aggregate reports of all adverse events (serious/not serious and 
expected, unexpected) for the DSMB and the IRB as required and for the FDA on an 
annual basis.  
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical 
study is to establish drug effect. 
Cases of pregnancy that occur during maternal or paternal exposures to investigational 
product or drug-delivery system should be reported. Data on fetal outcome and breast 
feeding are collected for regulatory reporting and drug-safety evaluation. 
 
8.5.1 Reporting of Serious Adverse Events  
Serious adverse events (SAEs) that are either life-threatening or which result in death 
must be reported by the PI to the IRB and the Medical Monitor via telephone, fax or 
email within one business day of discovery. The full report must be submitted to the IRB 
within 48 hours of initial notification. The Medical Monitor (or their delegate) will then be 
contacted by the PI and be informed of the details of the SAE, to determine if it meets 
the reporting requirement of a serious and unexpected suspected adverse reaction.  
Investigators are required to submit follow-up reports to the initial report as promptly as 
is feasible. The PI will submit a report of the SAE to the FDA within 15 calendar days of 
the event, if the event meets the reporting requirement of a serious and unexpected 
suspected adverse reaction. In those cases, the PI will also report the event to the 
DSMB. In all other cases, the PI will submit the report as part of periodic reporting to the 
DSMB and FDA. 
Events that are not life-threatening and do not result in death must reported to the IRB 
within 7 business days of discovery. 
The Medical Monitor will review causality (unrelated, not likely related, possibly related, 
probably related, definitely related) of the serious adverse event. The Medical Monitor 

 
 
 
 
 
 
 
46
may request further information if necessary and possibly request changes to the 
protocol or consent form as a consequence of the adverse event.  
Additionally, the PI will be responsible for reporting SAEs to the IRB within the time 
mandated by this IRB. The PI will inform all investigators of any safety updates or 
changes.  
SAEs occurring after a patient has taken the last dose of investigational product will be 
collected in the clinical data-collection database for 28 days after the last dose of 
investigational product, regardless of the investigator’s opinion of causation. Thereafter, 
SAEs are not required to be reported unless the investigator assesses the events were 
related to either investigational product, or a study procedure, and unexpected. 
  
8.5.2 Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are 
not listed in the Prescribing Information and that the investigator identifies as related to 
investigational product or procedure.  
 
8.5.3 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises 
that changes the investigator’s assessment of the event, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) 
should be submitted to the IRB. The investigator is responsible for ensuring that all SAE 
are followed until either resolved or stable.  
 
8.6 Notifications of SAEs/IND Safety Reports to the FDA 
Unexpected fatal or life-threatening adverse events that are related to the study drug, 
will be reported to FDA as soon as possible but no later than 7 calendar days following 
the sponsor’s initial receipt of the information. 
Unexpected serious adverse events that are related to the study drug but not fatal or 
life-threatening, will be reported to FDA as soon as possible but no later than within 15 
calendar days following the sponsor’s initial receipt of the information. 
Follow-up reporting: Any relevant additional information obtained by the sponsor that 
pertains to a previously submitted IND safety report will be submitted as a Follow-up 
IND Safety Report. Such report will be submitted as soon as the information is 
available, but no later than 15 calendar days after the sponsor receives the information. 
 
8.7 Study Stopping Rules 
There are some circumstances which potentially may arise, requiring temporary study 
stop. A serious adverse event, directly related to the use of study drug, will prompt a 
temporary stop to discuss the event with the DSMB and FDA. The IRB will be notified in 
accordance with CHOP IRB SOP 408. The study will proceed only with documented 
concurrence of the DSMB, FDA and the IRB, as applicable.  
 
The occurrence of two non-fatal SAEs directly related to use of the study drug or one 
death directly attributed to use of the study drug will stop the study. 
 

 
 
 
 
 
 
 
47
8.8 Safety Management and Monitoring Guidance 
The following Appendices should be followed. Appendices 9-12 in particular serve as 
guidance for management of abnormal laboratory values identified during screening or 
safety follow-up of enrolled individuals. 
 
 
Study schedule, Overall 
Appendix 1 
Study Timeline 
Appendix 2 
Dose Escalation Schedule for Patients with eGFR ≥60 mL/min/1.73 
m2 or Normal eGFR for Age <24 Months 
Appendix 3 
Dose Escalation Schedule for Patients with eGFR 30 - <60 
mL/min/1.73 m2 or for Age <24 Months with abnormal eGFR 
Appendix 4 
AGS severity scale 
Appendix 5 
Patient Daily Diary for AGS infants 0-6 months 
Appendix 6 
Patient Daily Diary for AGS > 6 months 
Appendix 7 
Clinical Laboratory Tests 
Appendix 8 
Management of Liver Enzyme Laboratory Values 
Appendix 9 
Management of Leukocyte associated laboratory testing and IgG 
Appendix 10 
Management of Anemia 
Appendix 11 
Management of Thrombocytopenia and Thrombocytosis 
Appendix 12 
Cutaneous LE Disease Area and Severity Index (CLASI) 
Appendix 13 
Dose tapering guidance 
Appendix 14 
Decision tree in case of infection suspicion or confirmation 
Appendix 15 
Concomitant medication approach in patients with AGS receiving 
baricitinib 
Appendix 16 
 
 
 

 
 
 
 
 
 
 
48
9 
STUDY ADMINISTRATION 
9.1 Treatment Assignment Methods 
9.1.1 Randomization 
There are no randomization procedures. 
 
9.1.2 Blinding 
There are no blinding procedures. 
 
9.1.3 Unblinding 
There are no unblinding procedures. 
  
9.2 Data Collection and Management 
9.2.1 REDCap for Study Data Management 
The study will utilize REDCap to provide a Web-based data collection, data 
management system. REDCap is an NIH-supported, broadly-used tool developed and 
continually improved by Vanderbilt University. CHOP has had very substantial 
experience in the implementation and support of REDCap data bases for clinical 
trials. Specifically, Dr. Vanderver already has in place a REDCap database designed 
specifically for AGS. Database fields correspond to expected disease complications 
and anticipated possible adverse outcomes. CHOP provides support for the 
management and curating of datasets from REDCap.  Especially important are reports 
to the Data and Safety Monitoring Board (DSMB) charged with ensuring the safety of 
study participants. Finally, the database is directly accessible to standard statistical 
packages such as SAS, SPSS, and STATA so that interim and final analyses can be 
conducted without the need to transport data. REDCap reports will monitor recruitment 
overall. It will warn of recruitment problems by plotting actual vs. expected screens, 
recruits and enrollees. 
 
9.2.2 Additional Study Data Management 
The study will also utilize OnCore Clinical Trials Management System and Advarra 
EDC, CHOP Research IS secured electronic data capture systems, which will be used 
for study scheduling, data collection and analysis (e.g. eCRFs), as well as billing and 
regulatory purposes. OnCore Clinical Trials Management System and Advarra EDC are 
secure electronic data capture systems with access controls and a data backup plan. 
The systems are password protected. Only study team members will have access to 
study documents, subject data and case report forms stored in these systems. Access 
to the systems is monitored and logged for review if needed. 
  
  
 
 

 
 
 
 
 
 
 
49
9.2.3 Data Security 
There are several layers of security that protect the data stored in REDCap and 
OnCore.  The first layer consists of network security, through firewalls, and is designed 
to limit access to authorized users and to deny access to all others. The firewall blocks 
malware and prevents flooding.  The second layer consists of database authentication.  
This limits access to the database to those individuals passing layer one who have an 
assigned database account and can enter the correct, suitably complex, user-defined 
password for that account.  The third layer consists of controlling a user’s capabilities, 
what a user can see and do, based on the user’s role in each investigation.  Each user 
needing access to the data for a study must be included on the list of key staff for that 
specific study in the protocol and must be assigned a study role.  If a user is not in the 
key staff list of the study s/he will not be granted access to that study’s data even if s/he 
has a valid password associated with another study.  Key staff will only be allowed to 
perform those tasks that are dictated by the person’s defined role in the study.  For 
instance, a person who enters data will only be able to add records to specific data files; 
s/he cannot peruse or make changes to existing records in the database.  Only those 
persons who have clinical responsibilities for the patient would be able to see patient 
identifying information.  There is provision for the PI to be able to over-ride, to widen or 
narrow, the capabilities assigned based on study role. 
Lastly, to protect patient confidentiality, study research data is coded and separated 
from all patient identifying information.  The confidential data is stored separately and 
the information is encrypted to offer additional protection.  Each research participant in a 
study is assigned an anonymous participant ID number that can be used to link together 
a participant’s de-identified research records but not to link directly to the confidential 
identifying data.  Since there must be a way to link to that data to identify patients for 
scheduling and mailings, etc., a second arbitrary number called a universal identifier is 
assigned to each participant’s confidential data record.  That number is linked to the 
participant ID via a second translation file that is also encrypted.  Therefore, in the 
extremely unlikely event that an unauthorized person gained access to the confidential 
data file all s/he would see is gibberish without having the appropriate key to decrypt the 
data. Likewise, all transmissions to and from REDCap are sent using secure HTTP 
(HTTPS), which encrypts all transmissions so that even if they were intercepted their 
content would be unreadable by all but the intended recipient. 
There are also two other components to security and they are monitoring and system 
administration.  The network is closely monitored and all activity is logged.  Both the real 
time monitor and the logs are reviewed by eye and by computer to identify suspicious 
activity so that it can be dealt with appropriately.  Furthermore, all access to research 
data is audited and all activities are logged so that if a problem occurs it will be possible 
to identify who was responsible and how it happened.  The system and database 
software are kept up-to-date with the latest security protections released for the 
operating system and for the database. These measures help us to keep ahead of the 
threats to security or to close loopholes before they can be more widely exploited. 
Finally, there is excellent physical security; access to the systems is key pad controlled, 
there is a backup generator to provide power to keep systems operating in the event of 

 
 
 
 
 
 
 
50
power failure, all computer rooms housing database and web servers are 
environmentally-controlled and protected against flood and fire.  
 
9.2.4 Data Acquisition and Entry 
Data collection for this study will be accomplished with online electronic case report 
forms.   
• 
On-line forms will be developed that contain the requisite data fields.   
• 
For each subject enrolled all study-related visits of the enrollment, diagnostic, 
application, observation, termination and follow-up phases will be recorded in the 
CRF. This CRF must be completed and signed by the investigator for every subject 
on whose behalf written informed consent was given. This also applies to subjects 
who fail to complete the study. If a subject is being withdrawn from the study by 
his/her parent(s)/legal guardian(s), the reason must be stated in the CRF, if the 
parent(s)/legal guardian(s) are willing to provide such reason. If a subject is 
withdrawn from the study because of a limiting AE, reasonable efforts should be 
made to clearly document the outcome.  
• 
All subjects will be identified by their subject number.  
• 
Each investigator will be responsible for ensuring that the identification of his/her 
subjects is possible at any time.  
• 
The investigator will use CRF Completion Guidelines to ensure that data is complete 
and accurate. These guidelines will provide instructions on how to complete, correct, 
and archive final copies of the CRFs. 
• 
Prior to the beginning of the study, the investigator must establish a list of the 
individuals with trial related duties and of the persons authorized to make entries and 
data changes in the CRFs. 
• 
These persons will be listed, including details on their function in the study, their full 
names, initials, and signatures, and the date of their assignment to (and, if 
applicable, their demission from) their respective duties on this study, on the center 
sample signature page in the investigator’s file. 
 
9.2.5 Data Editing 
A number of data checks and procedures may be applied during data collection that 
either prevent errors or detect them with the requirement for later review and 
adjudication. No matter what the data source all data must pass through all predefined 
data checks and all potential errors must be reviewed and corrected or accepted with 
comment. Any discrepancies are reported in a data exception feedback report for 
correction and are monitored to ensure that they are accepted or corrected. Predefined 
procedures and data checks include:  
• 
choosing forms and participants for data entry from the list of predefined enrollees 
avoiding the errors that can occur when ID numbers are entered directly on forms; 
• 
implementing validation and consistency checks before data are sent to the 
database to allow correction but logging of all uncorrected exceptions for required 
later review; and 

 
 
 
 
 
 
 
51
• 
checking for and recording on each form the rate of missing data that can be used to 
set criteria for subsequent forms processing, e.g. to reject forms with high missing 
data rates from entering the database; and  
• 
flag out of range values 
• 
creating a context sensitive comment window that allows subsequently retrievable 
text to be linked to any form or data item, e.g., to explain an unusual data response.   
 Web-based, forms allow data to be viewed and edited. Quality assurance checks are 
applied during data entry and editing.  In addition to maintaining a time-stamped audit 
trail of all logins and transactions, the system has the capability to be proactive, for 
example in requiring all unflagged data corrections be accompanied by a justification as 
well as to be adjudicated, reviewed, accepted or rejected, by a designee. Together 
these options and procedures promote a high degree of completeness, and accuracy of 
study data.  
 
9.2.6 Data Entry Training  
Data entry training will be conducted on line using the REDCap database and OnCore 
and Advarra databases. Study coordinators will be trained and certified in on-line use of 
the REDCap and OnCore databases. Training sessions will be scheduled and 
organized by members of the study team.  
 
9.2.7 Data Quality Assessment (QA) 
Data quality is assessed at the data entry point using intelligent review and controls 
during on-line data entry or edits via study forms. QA reports assess data quality post-
data entry. Data quality begins with the design of the data collection forms and 
procedures and incorporates reasonable checks to minimize transcription and omission 
errors. Equally important quality assurance measures are the internal checks for 
reasonableness and consistency that will be implemented via simple tabulations and 
cross tabulations that should reveal any remaining data quality issues. 
 
9.3 Confidentiality 
By conducting this study, the investigator pledges that he/she will keep all information 
pertaining to the study strictly confidential, including data generated from this study, 
except as exempted for regulatory purposes.  
Blood and urine samples will be collected and diagnostic records will be reviewed.  Data 
recorded will include demographics, clinical summary, diagnostic tests and study results. 
All research data, including identifiers, will be accessible only to the research team and as 
required by law.  
 
9.4 Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
A DSMB has been assembled by the investigators.  This Board is responsible for safety 
and accuracy monitoring of the data entered by the investigators. The DSMB will 
regularly evaluate trial performance, monitor interim data for safety and effectiveness of 
study regimens, review any protocol modifications, and advise the investigators 

 
 
 
 
 
 
 
52
regarding early termination or continuation of a study based on the interim monitoring or 
scientific findings. The DSMB will receive and respond to reports of any serious adverse 
events (SAEs) and will be immediately notified of fatal or life-threatening events. Based 
on the review of safety, efficacy, and performance data, the DSMB will make 
recommendations regarding conduct of the study. It is expected that the DSMB will 
meet as per the DSMB Charter.  
 
9.4.2 Risk Assessment 
9.4.2.1 
Risks associated with Baricitinib 
Baricitinib is Janus Kinase inhibitor which blocks the intracellular signaling response of 
interferon by limiting downstream activation of the interferon receptor.  Janus Kinase 
inhibitors, including baricitinib, may therefore have risks associated with infection, as 
well as other serious risks. These are detailed below, and further information is 
available in prescribing information. 
 
9.4.2.1.1 Serious Infections and Viral Reactivation 
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, 
viral, or other opportunistic pathogens have been reported in rheumatoid arthritis 
patients receiving baricitinib. The most common serious infections reported with 
baricitinib included pneumonia, herpes zoster, and urinary tract infection (see Adverse 
Reactions).  
Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, 
esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, 
cytomegalovirus, and BK virus were reported with baricitinib. Some patients have 
presented with disseminated rather than localized disease and were often taking 
concomitant immunosuppressants such as methotrexate or corticosteroids. 
As of March 2020, fungal pneumonia was reported in a single AGS patient receiving 
baricitinib and also receiving concomitant therapy with corticosteroids during the Lilly 
expanded access program. Vigilance for infections should remain high in particular in 
children with any concomitant medications increasing immunosuppression, or 
hematologic parameters suggestive of immunosuppression. 
Prophylaxis for serious infections will be recommended based on CD4, IgG, ANC and 
ALC levels as per section 4.6. 
 
To minimize these risks, screening includes careful assessment of infections prior to 
drug initiation, including HIV, hepatitis, tuberculosis, HSV, CMV, EBV, and BK virus. In 
addition, ongoing evaluations, including clinical assessments for infection, and 
laboratory testing for HSV (IgG/IgM), CMV PCR, EBV PCR and tuberculosis (via 
quantiferon gold testing, only for patient in endemic regions) during treatment, will be 
conducted as clinically indicated.  
Patients will be monitored for BK viremia at baseline, and every six months until they 
reach two years of age. Over two years of age, complete follow-up BK testing will be 
performed if any of the following is observed: blood in urine not explained by a urinary 

 
 
 
 
 
 
 
53
tract infection (as defined by greater than 10 RBCS in HPF), equal to or greater than 1+ 
protein on a first morning urine sample not explained by a urinary tract infection 
(positive), decrease in eGFR (30 - <60 mL/min/1.73 m2).  
Children with AGS are at risk of respiratory, skin and urinary tract infections as part of 
their disease. Unless these infections fall into the categories below, there will not be 
drug discontinuation for these events. Patients will receive treatment as clinically 
indicated for these infections. Discontinuation of baricitinib has been associated with 
neurologic decline in patients with AGS17, leading to greater caution around holidays 
from drug therapy in the context of acute infections. 
Certain categories of infections will require specific management: 
Serious infections are defined as those resulting in or occurring during 
hospitalization, or need for parenteral antimicrobial treatment. In these cases, the 
diagnostics and treatment plan will be discussed with local infectious disease team for 
decisions regarding continuation, decrease or interruption of study treatment. All events 
where infection is associated with hospitalization or need for parenteral antimicrobial 
treatment will be reported to the DSMB and IRB as a SAE within 24 hours of learning of 
the event. Patients will receive treatment as clinically indicated regardless of treatment 
decisions for baricitinib. 
Disseminated/complicated herpes zoster, for which drug cessation will occur until 
improvement in symptomatic herpes zoster infection occurs (resolution of PCR positive 
serologies or all lesions crusted) as confirmed by local infectious disease team. 
Disseminated/complicated herpes zoster is defined as multidermatomal involvement in 
cases of reactivation, central nervous system involvement or systemic involvement 
including hepatitis or pneumonitis).  After improvement, baricitinib may be resumed. 
Herpes zoster that is not confirmed, is self resolving, limited to skin without CNS, 
hepatic or pulmonary involvement, will result in discussion with local infectious disease 
team but will not result in immediate drug discontinuation. The infection will be managed 
as clinically indicated. Patients will receive treatment as clinically indicated regardless of 
treatment decisions for baricitinib. All events of disseminated/complicated herpes zoster 
will be reported to the DSMB and IRB within 24 hours of learning of the event as a 
reportable event.   
Viral reactivation, including EBV/CMV reactivation.  In these cases, the 
diagnostics and treatment plan will be discussed with local infectious disease team for 
decisions regarding continuation, decrease or interruption of study treatment. Viral 
reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were 
reported in clinical studies with baricitinib. If a patient develops 
disseminated/complicated herpes zoster, we will interrupt treatment until the episode 
resolves (i.e. until symptomatic improvement of the herpes zoster occurs). EBV and 
CMV may also be reactivated during treatment, and both EBV and CMV will be 
monitored during study safety laboratory testing (via PCR) if hematologic or hepatologic 
parameters suggest infection. If a patient develops clinically relevant reactivation, we 
will notify local infectious disease team to establish whether to continue, decrease or 
interrupt treatment until improvement is seen in viral titers or organ involvement (see 
Appendix 15). All events of EBV/CMV reactivation will be reported to the DSMB and IRB 

 
 
 
 
 
 
 
54
within 7 days of learning of the event as a reportable event. Patients will receive 
treatment as clinically indicated regardless of treatment decisions for baricitinib. 
 
Infections occurring in cases where ANC, ALC, IgG, CD4 are at levels that need 
additional monitoring as defined in the protocol. In these cases, the diagnostics and 
treatment plan will be discussed with local infectious disease team for decisions 
regarding continuation, decrease or interruption of study treatment. All events will be 
reported to the DSMB and IRB within 7 days of learning of the event as a reportable 
event. Patients will receive treatment as clinically indicated for these infections 
regardless of treatment decisions for baricitinib. 
Appendix 15 details a decision tree in case of suspicion or confirmation of infection. 
 
9.4.2.1.2 Tuberculosis 
Patients will be evaluated for latent or active infection prior to administration of 
baricitinib. Baricitinib should not be given to patients with active TB. We will consider 
anti-TB therapy prior to initiation of baricitinib in patients with a history of latent or active 
TB in whom an adequate course of treatment cannot be confirmed, and for patients with 
a negative test for latent TB but who have risk factors for TB infection.  
 
 
Table 4: Adverse Reactions occurring in greater than or equal to 1% of Baricitinib 
2 mg and Baricitinib 4 mg Treated Patients in Placebo-Controlled Trials 
 
 
 
 
 
 
 
 
 
 
a. Includes acute sinusitis, acute tonsillitis, chronic tonsillitis, epiglottitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, 
pharyngotonsillitis, rhinitis, sinobronchitis, sinusitis, tonsillitis, tracheitis, and upper respiratory tract infection. 
b   Includes eczema herpeticum, genital herpes, herpes simplex, ophthalmic herpes simplex, and oral herpes. 
Additional adverse drug reactions occurring in fewer than 1% of patients: acne 
9.4.2.1.4 Malignancy and Lymphoproliferative disorders 
Non-melanoma skin cancers (NMSCs) have been reported in patients treated with 
baricitinib. Periodic skin examination is recommended for patients who are at increased 
risk for skin cancer. 
9.4.2.1.5 Thrombosis 
Thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), 
has been observed at an increased incidence in adult patients treated with baricitinib 
compared to placebo. In addition, arterial thrombosis events in the extremities have 
been reported in clinical studies with baricitinib. Many of these adverse events were 
 
 
 
 
 
Events 
Weeks 0-16 
Placebo 
 
n=1070 (%) 
Baricitinib, 2 mg 
n=479(%) 
Baricitinib 4 mg 
n=997 (%) 
Upper respiratory tract infectionsa 
11.7 
16.3 
14.7 
Nausea 
1.6 
2.7 
2.8 
Herpes simplexb 
0.7 
0.8 
1.8 
Herpes zoster 
0.4 
1.0 
1.4 
 

 
 
 
 
 
 
 
55
serious and some resulted in death. There was no clear relationship between platelet 
count elevations and thrombotic events. As of March 2020, in one patient with AGS, 
thrombosis of the pulmonary vasculature, associated with previously unrecognized 
severe pulmonary hypertension, caused death. Thus, baricitinib should be used with 
caution in patients who may be at increased risk of thrombosis, and in particular in AGS 
patients with underlying pulmonary hypertension. In AGS, regular screenings for 
pulmonary hypertension will occur according to clinical recommendations. If clinical 
features of DVT/PE or arterial thrombosis occur, patients should be evaluated promptly 
and treated appropriately. 
9.4.2.1.6 Gastrointestinal Perforations 
Events of gastrointestinal perforation have been reported in clinical studies with 
baricitinib, although the role of JAK inhibition in these events is not known. Baricitinib 
should be used with caution in patients who may be at increased risk for gastrointestinal 
perforation (e.g., patients with a history of diverticulitis). Patients presenting with new 
onset abdominal symptoms should be evaluated promptly for early identification of 
gastrointestinal perforation. 
9.4.2.1.7 Bone growth 
 
During a juvenile rat study completed to support the dosing of baricitinib to patients 1 to 
<12 years, there were reductions in overall growth evidenced by lower body weights. 
Additional skeletal effects were observed in the juvenile rat study including marginal-to 
slight decreases in femur and tibia size as well as an apparent acceleration of normal 
maturation ossification centers. These findings were not associated with premature 
closure of growth plates or other functional consequences. Microscopically, there was a 
focal increase in trabecular bone. The effects of baricitinib in the pediatric population is 
not characterized. In addition, it should be noted that children with AGS have decreased 
overall growth which is assumed to be related to their chronic inflammatory disease. 
 
9.4.2.2 
Laboratory Abnormalities 
9.4.2.2.1 Neutropenia  
Treatment with baricitinib was associated with an increased incidence of neutropenia 
(ANC less than 1000 cells/mm3) compared to placebo. CBC will be checked in 
individuals with ongoing treatment with baricitinib according to the study schedule and 
management of laboratory abnormalities will be performed according to Appendix 10. 
We will avoid initiation, decrease (Appendix 14) or interrupt baricitinib treatment in 
patients according to Appendix 10.  Discussion with the study staff included in the 
Dysregulated Immune Response Team will help to determine if this complication is 
caused by AGS (see Appendix 10 for guidance). Testing will be performed as detailed 
in Appendix 10 and prophylaxis for individuals with abnormal values will be 
implemented as discussed in this section. 
9.4.2.2.2 Lymphopenia  
ALC less than 500 cells/mm3 were reported in baricitinib clinical trials. Lymphocyte 

 
 
 
 
 
 
 
56
counts less than the lower limit of normal were associated with infection in patients 
treated with baricitinib, but not placebo. CBC will be checked in individuals with ongoing 
treatment with baricitinib according to the study schedule and management of 
laboratory abnormalities will be performed according to Appendix 10. We will avoid 
initiation, decrease (Appendix 14) or interrupt baricitinib treatment in patients according 
to Appendix 10. Discussion with the study staff included in the Dysregulated Immune 
Response Team will help to determine if this complication is caused by AGS (see 
Appendix 10 for guidance). Testing will be performed as detailed in Appendix 10 and 
prophylaxis for individuals with abnormal values will be implemented as discussed in 
this section. 
 
In addition, IgG and lymphocyte subset testing will be performed as detailed in section 
4.6 and prophylaxis for individuals with abnormal values will be implemented as 
discussed in Appendix 10. 
9.4.2.2.3 Anemia  
Decreases in hemoglobin levels to less than 8 g/dL were reported in baricitinib clinical 
trials. CBC will be checked in individuals with ongoing treatment with baricitinib 
according to the study schedule and management of laboratory abnormalities will be 
performed according to Appendix 11. We will avoid initiation, decrease (Appendix 14) or 
interrupt baricitinib treatment in patients according to Appendix 11. Discussion with the 
study staff included in the Dysregulated Immune Response Team will help to determine 
if this complication is caused by AGS (see Appendix 11 for guidance). Testing will be 
performed as detailed in Appendix 11 and prophylaxis for individuals with abnormal 
values will be implemented as discussed in this section. 
9.4.2.2.4 Liver Enzyme Elevations  
Treatment with baricitinib was associated with increased incidence of liver enzyme 
elevation compared to placebo. Increases to greater than or equal to 5x and greater 
than or equal to 10x upper limit of normal (ULN) were observed for both ALT and AST in 
adult patients in baricitinib clinical trials. Additionally, without treatment, increases of 
both ALT and AST are seen in one-third of individuals affected by AGS. Liver function 
and enzyme testing will be checked in individuals with ongoing treatment with baricitinib 
according to the study schedule and management of laboratory abnormalities will be 
performed according to Appendix 9. Discussion with the study staff will help to 
determine if this complication is caused by AGS (see Appendix 9 for guidance).  
9.4.2.2.5 Lipid Elevations  
Treatment with baricitinib was associated with increases in lipid parameters, including 
total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein 
(HDL) cholesterol in adult patients. Lipid parameters will be checked in individuals with 
ongoing treatment with baricitinib according to the study schedule. We will manage 
patients according to clinical guidelines for the management of hyperlipidemia and with 
the assistance of study staff.  
 

 
 
 
 
 
 
 
57
The following guidelines will be considered: 
• 
If TG >400, repeat fasting sample. If still elevated >400, refer to a provider with 
experience in lipid management. 
• 
If LDL>160, refer to a provider with experience in lipid management. 
• 
If HDL<25, refer to a provider with experience in lipid management. 
 
9.4.2.3 
Vaccinations 
We will avoid use of live vaccines in patients undergoing treatment with baricitinib. 
Infants who should receive live vaccines during the period of baricitinib treatment will be 
counseled by a physician other than the investigators (e.g. Medical Monitor) on the 
relative risks of vaccination versus treatment without vaccination. Whenever medically 
safe, we will update immunizations in agreement with current immunization guidelines 
prior to initiating baricitinib therapy. Patients will not be treated earlier than 4 weeks after 
receiving live vaccines with the exception of the oral rotavirus vaccination, for which 
patients will not be treated earlier than 2 weeks after receiving vaccination, and the 
Typhoid and BCG vaccine which will require 12 weeks after vaccination prior to 
receiving baricitinib. 
 
9.4.2.4 
Risks associated with Blood Testing 
Needle punctures for blood draws may cause some pain, bleeding or bruising and 
rarely, may cause fainting or infection. This risk is similar to the risk encountered by 
affected patients during routine clinical care. 
9.4.2.5 
Risks of Physical Exam including functional assessments 
There are no physical risks associated with a physical exam or functional assessments 
but it may cause momentary embarrassment or discomfort. This risk is similar to the risk 
encountered by affected patients during routine clinical care. 
9.4.2.6 
Risk of Interview/Questionnaires including functional assessments 
There are no physical risks associated with questionnaires or functional assessments 
but it may cause momentary embarrassment or discomfort. This risk is similar to the risk 
encountered by affected patients during routine clinical care. 
9.4.2.7 
Breach of Privacy and Confidentiality 
As with any study involving collection of data, there is the possibility of breach of 
confidentiality of data. Every precaution will be taken to secure participants' personal 
information to ensure confidentiality. At the time of participation, each participant will be 
assigned a research program identification number. This number will be used on data 
collection forms, blood samples, and in the database instead of names and other private 

 
 
 
 
 
 
 
58
information. A separate list will be maintained that will link each participant's name to 
the research program identification number for future reference and communication. 
9.5 Benefits 
9.5.1 Potential Benefits of Trial Participation 
Based on existing preliminary data (see introduction) it is expected that some patients 
will benefit from trial participation. Benefits may include control of systemic features 
including improvement of abnormal liver and hematologic parameters, improved 
comfort, improvement in skin manifestations and in some cases, improved neurologic 
function. 
 
9.5.2 Risk-Benefit Assessment 
Based on existing preliminary data (see introduction) the Risk-Benefit assessment 
justifies proceeding with providing baricitinib in a clinical trial setting to individuals 
affected by AGS. Baricitinib has been generally well tolerated with improvement in 
measures of comfort and skin involvement, with additional neurologic benefit in a subset 
of affected individuals. 
Additionally, study staff will make every effort to limit other risks associated with study 
participation including the following measures: 
• 
The drug will be handled by the respective site investigational drug pharmacy and 
will be dispensed by that pharmacy.  
• 
The participants and their families will be provided psychological and emotional 
support to deal with the results of the diagnostic testing.  
• 
Confidentiality is protected to the full extent required by law and applicable local, 
State and Federal regulations and guidance including HIPAA.  
• 
All medical records, including case report forms, will be kept in locked files 
accessible only to the health professionals involved in the clinical research or 
responsible for the participant’s care, governmental agencies (e.g., FDA, NIH), and 
local convening authorities (e.g., IRB, DSMB) for the purpose of audit regarding 
scientific validity and/or aspects pertaining to the ethical conduct of human clinical 
investigation. Identifier data are not released without the parent’s/participant’s 
knowledge and consent. Electronic databases with identifier data are user 
ID/password protected.  
• 
The results of the study will be shared with the participants of the study as soon as 
they become available.  
9.6 Recruitment Strategy 
Participants will be recruited by advertisement via testing laboratories, family advocacy 
organizations, self-referral, or participation in a clinical leukodystrophy program. 
Patients’ families will be first contacted by non-study personnel to discuss the possibility 
of participating in a clinical trial. If the patient is also a patient of the investigators, study 
participation will be discussed with the Medical Monitor. Should the family be interested, 
patients and families will be invited to contact the investigative team to discuss 
participation and ICF documents will be shared with the family. Should the family 
continue to be interested, the family will be invited to visit CHOP. Medical records will be 

 
 
 
 
 
 
 
59
collected for verification of study eligibility, including mutation status as part of clinical 
standard and care and not as part of this research, after release of information and after 
consent for screening (see below). 
 
9.7 Informed Consent/Assent and HIPAA Authorization 
During the screening period, telephone consent may be obtained by study staff to 
facilitate the explanation of the study procedures and screening visit. In all cases, if a 
telephone consent was obtained during the screening period, written consent will be 
obtained by the investigator or designee during the enrollment visit. 
The investigator or designee will meet with the parent(s) or legally authorized 
representative to describe the study. Parents will be brought to a private, quiet room 
where the benefits and risks of the study will be explained thoroughly, and any 
questions will be answered. The investigator or designee will then give the parent(s) 
time to read the consent form and consider participation. The investigator or designee 
will return to answer questions and ensure that the legally authorized representative 
understands the information provided and obtain informed consent. 
 
For patients transferred from the JAGA Compassionate Use study (CHOP IRB Study 
#13205), informed consent may occur remotely, by video or phone, if the patients or 
their parent(s) or legally authorized representative(s) are not able to come on-site. In 
this case, informed consent documents will be sent by mail, secure email or secure 
facsimile (from a fax device only accessible to the study team or RightFax, a CHOP-
approved fax application) to the legally authorized representative ahead of time, prior to 
the video of phone visit, to give them time to read the consent form and consider 
participation. During the phone or video visit, the investigator or designee will answer 
questions and ensure that the legally authorized representative understands the 
information provided. If video visits are used, they will be completed on myCHOP, a 
CHOP-secure system. If the legally authorized representative is willing to participate, 
they will be asked to sign the consent form at the end of the visit, and to return the 
signed consent form by mail, secure email or facsimile (to a fax number only accessible 
to the Study Team), for signature of the investigator or designee. Once the consent form 
is fully signed, a copy will be provided to the legally authorized representative by mail, 
secure email or secure facsimile (from a fax device only accessible to the study team or 
RightFax, a CHOP-approved fax application). 
 
For subjects who did not transition to this investigator-initiated study because they 
obtained commercial supply or discontinued participation in the JAGA Compassionate 
Use study (CHOP IRB Study #13205) will be consented via a separate consent form to 
permit inclusion of their data.  
 
Consent for all patients may also take place via the Part 11 compliant REDCap e-
consent feature.  
 
Informed consent documents will be available in English. If the parents are only fluent in 
another language, and the site has a standard operating procedure for informed 
consent in that language (such as an on-call interpreter, abbreviated consent form in 

 
 
 
 
 
 
 
60
English) and the site IRB has approved the process for this study in advance, non-
English speaking parents/guardians will also be included. 
 
To obtain consent from patients with Limited English Proficiency (LEP) using the Part 11 
compliant REDCap e-consent feature, a Short Form template will be made available in 
REDCap in the appropriate language. The interpreter/witness who will have attended 
the consent visit will also be able to sign the consent using the Part 11 compliant 
REDCap e-consent feature. 
 
The investigator is responsible for ensuring that the patient or parent understands the 
potential risks and benefits of participating in the study, including answering any 
questions the patient or parent may have throughout the study and sharing in a timely 
manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial. 
The ICF will be used to explain the potential risks and benefits of study participation to 
the patient or parent in simple terms before the patient is entered into the study, and to 
document that the parent is satisfied with his or her understanding of the risks and 
benefits of participating in the study and desires to participate in the study. 
The investigator is responsible for ensuring that informed consent is given by each  
legal representative. This includes obtaining the appropriate signatures and dates on 
the ICF prior to the performance of any study procedures and prior to the administration 
of investigational product. A legal representative must give informed consent for a child 
to participate in this study. 
As used in this protocol, the term “informed consent” includes all consent given by a 
legal representative. 
• 
It is the responsibility of the investigator to ensure that no subject is enrolled in any 
study-related examination or activity before written informed consent has been 
obtained.  
• 
Written informed consent will be obtained in compliance with 21 CFR Part 50 and 
the ethical principles that have their origin in the Declaration of Helsinki.  
• 
The subject’s legal representative(s) will be informed that they are completely free to 
refuse to enter the study or to withdraw from it at any time.  
• 
Subjects whose legal representative(s) refuse to give written informed consent or 
withdraw their informed consent later on must not be included into the trial or must 
be excluded from further participation, respectively. Before personally dating and 
signing the informed consent form, the subject’s legal representative(s) will be 
informed in detail by the investigator or a designee of the investigator about all 
pertinent aspects of the trial according to 21 CFR Part 50 and ICH GCP.  
• 
The subject’s legal representative(s) should be given sufficient time to request 
further details about the trial before signing the informed consent form, in 
accordance with the ICH GCP Guidelines (1997).  
• 
The receipt of the informed consent from the legal representative(s) must be 
documented on the appropriate page of the subject’s CRF and in the source 
documents.  
• 
One copy of the consent form signed and dated by the subject’s legal 
representative(s) and by the physician who informed the legal representative(s) will 

 
 
 
 
 
 
 
61
be kept at the study site; a second copy will be provided to the subject’s legal 
representative(s). 
• 
Written HIPAA authorization will be obtained from the combined informed consent 
form. 
 
Potential subjects can also be pre-screened over the phone, in which case patients or 
their guardians will undergo telephone consent, to explain the purpose and procedure of 
the study. Formal written consent will be obtained at Visit 1. 
9.7.1 Waiver of Consent and HIPAA Authorization 
Waivers of consent/parental persmission, assent, and HIPAA authorization are 
requested for participants previously enrolled in the JAGA Compassionate Use study 
(CHOP IRB #16-013205) that were lost to follow-up and unable to provide consent for 
inclusion of their data as discussed in Section 9.7. A subject will be considered lost to 
follow-up if five (5) attempts (on separate days) to contact the subject by phone or email 
have been unsuccessful. A waiver of consent and HIPAA authorization is requested for 
continued use of the existing data. 
Inclusion of these patients’ data is important for baseline comparison, overall 
understanding of efficacy and safety in this ultra rare disease and ensuring 
generalizability of results. Only up to a Limited Data Set will be included in the electronic 
data capture system. 
 
The procedures for these participants is limited to review of medical and research 
records and therefore the risks are minimal and limited to breach of confidentiality, their 
inclusion would not affect subjects’ rights or welfare, and providing follow up information 
after participation is not applicable; as aforementioned, all eligible subjects and their 
data must be included in order to ensure generalizability of the results and the integrity 
of the data; data and PHI must be included in an identifiable format in order to link the 
data across timepoints and between the research/medical records and because there is 
overlap between the investigative teams between the two studies. 
 
The waiver is requested in accordance with 45 CFR 46.116(d): 
1) The research (continued use of the existing data) involves no more than minimal 
risk to the subjects; 
2) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects; 
3) If the research involves using identifiable private information or identifiable 
biospecimens, the research could not practicably be carried out without using 
such information or biospecimens in an identifiable format; 
4) The research could not practicably be carried out without the waiver or alteration, 
and 
5) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
 

 
 
 
 
 
 
 
62
9.7.2 Waiver of Assent 
The capability of all of the children is so limited that they cannot reasonably be 
consulted and the intervention involved in the research holds out a prospect of direct 
benefit that is important to the health or well-being of the children and may be 
available only in the context of the research. A waiver of assent is approved by the 
CHOP IRB under 45 CFR 46.408(a) / 21 CFR 50.55(c)(1). 
 
9.8 Compliance 
9.8.1 Regulatory Compliance 
This clinical trial will be conducted in accordance with the protocol, the ICH Harmonized 
Tripartite Guideline “Note for Guidance on Good Clinical Practice,” and the applicable 
local regulatory requirements. This study will be conducted in accordance with 
consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines, the International Conference on Harmonization GCP 
Guideline applicable laws and regulations. 
 
9.8.2 Investigator Assurances 
Audits shall ensure that the study is planned, conducted, evaluated, and reported 
according this protocol and the applicable SOPs of the Coordinating Center, the ethical 
principles that have their origin in the Declaration of Helsinki (1996), the requirements of 
the ICH Harmonized Tripartite Guidelines.  
Audits shall also ensure that the documentation of the study is available, complete, 
organized, and valid. 
The investigator agrees to give the study monitor access to all relevant documents, 
including source documents, for review. The same applies in case of an inspection of 
federal authorities or the relevant IRB. 
 
9.8.3 Records Retention and Requirements 
The sponsor must archive all essential records and documents including but not limited 
to medical records, informed consent, and identification codes for subjects and other 
original records. These documents of the study will be retained in accordance with FDA 
record retention requirements, and will comply with CHOP policy A-3-9 for data 
retention. 
 
9.8.4 Financial Disclosure 
Financial disclosure information will be collected per Part 54 of Title 21 of the CFR and 
ICH E6. In addition, the site investigators must provide to the Study PI a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the study. 
 

 
 
 
 
 
 
 
63
9.8.5 Regulatory Files 
Prior to beginning the study, the principal investigator and site investigators will be 
asked to comply with ICH E6 8.2 and Title 21 of the CFR by providing the following 
essential documents, including but not limited to: 
• An original investigator-signed Investigator Agreement page of the protocol 
• An IRB-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study 
that is to be provided to the subject or legal guardians 
• IRB approval of the protocol and amendments 
• Form FDA 1572, fully executed, and all updates on a new fully executed form 
FDA 1572, Curriculum vitae (CV) for the principal investigator and each sub 
investigator listed on Form FDA 1572. Current licensure must be noted on the 
CV. They will be signed and dated by the principal investigators and sub 
investigators at study start up, indicating that they are accurate and current. 
• Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under Part 54 of Title 21 
of the CFR and ICH E6. In addition, the Investigators must provide to the study 
PI a commitment to promptly update this information if any relevant changes 
occur during the course of the investigation and for 1 year following the 
completion of the study. 
• Laboratory certifications and normal ranges for any test or assay being 
performed. 
 
9.8.6 Monitoring 
The study will be monitored by the sponsor and co-investigators. Prior to trial initiation, 
trial readiness will be confirmed by the Office of Research Compliance (ORC) of CHOP, 
as assessed by the Pre-Trial Monitoring Visit.  Periodic institutional monitoring will also 
be conducted according to ORC guidelines.  
The investigator will ensure that the study team monitors according to the relevant 
standard operating procedures (SOPs) and GCP guidelines on a periodic basis to verify 
that data entries into the CRF are correct and that the study is conducted in accordance 
with this protocol. 
 
9.8.7 Modification of the Protocol 
Protocol modifications that affect the safety of the subjects or that alter the scope of the 
investigation, the scientific quality of the study, the experimental design, dosages, 
assessment variable(s), the number of subjects treated, or the subject selection criteria 
may be proposed by the principal investigator and the Medical Monitor. Any change to 
the protocol can be made only in the form of a written amendment to this study protocol. 
Such amendments must be approved by the CHOP IRB, and the FDA notified. 
 
9.8.8 Protocol Violations 
Protocol violations or deviations are any non-adherences to the procedures outlined in 
this document and include, but are not limited to, late evidence of exclusion criteria, 

 
 
 
 
 
 
 
64
missed evaluations, incorrect timing of evaluations or dosing, and intake of inadmissible 
medication. After a subject has been enrolled, it is the investigator’s responsibility to 
make any reasonable effort to avoid and, if necessary, correct protocol deviations. 
Major protocol violations will be reported to the DSMB at the time of a meeting, the IRB 
and the FDA. All protocol violations will be listed and the admissibility of the subjects’ 
data will be discussed with the Medical Monitor prior to the statistical analysis. In case 
any emergency or AE occurs that requires a protocol deviation in the particular case, 
the investigator should contact the Medical Monitor and DSMB as soon as possible to 
enable a decision on whether the subject’s participation in the study may be continued. 
 
9.9 Payment to Subjects/Families 
There will be no payment or re-imbursement to families or subjects. 
 
10 PUBLICATION 
Data sets will be made available to the scientific community after publication(s) of 
planned analyses (as set forth in the protocol) of the clinical trial results or no later than 
3 years after the final visit of the last participant to a clinical trial site, whichever comes 
first. Data obtained in this trial will be presented in national and international meetings 
and will be published in the medical literature with no delays. The investigators are not 
under any agreement with the provider of the drug to limit or delay the publication of 
data from this trial. 
 
 

 
 
APPENDIX 
Appendix 1. Study Schedule, Overall 
 
 
 

 
 
Appendix 2. Study Timeline* 
Procedures performed solely for research purposes are indicated in bold text 
Screening 
Baseline -
Initial 
dosing 
Treatment 
Early 
Termination 
Safety 
Closeout 
Visit number 
Required 
1 
2 
4p 
201p 
204o, 207p, 
210o 
212p, 213o, 214p, 215o, 
216p, 217o, 218p, 219o, 
220p, 221o, 222p, 223o, 
224p, 225o, 226p, 227o, 
228p, 229o, 230p,231o  
ETap  
801q 
Optionalq 
3 
5 
202, 203, 
205, 206, 
208, 209, 
211 
212A, 213A, 214A, 
215A, 216A, 217A, 
218A, 219A, 220A, 
221A, 222A, 223A, 
224A, 225A, 226A, 
227A, 228A, 229A, 
230A 
Weeks from 
enrollment 
4 to .5  
0 
2 
4 
8 
12 
16 to 52b 
60 to 288c  
— 
292 
Number of days 
at visit 
28 to 2 
Variabled 
1-5 
1-5 
1-5 
1-5 
1-5 
1-5 
1-5 
1-5 
Visit window 
(days)e 
— 
2 
+2 
+2 
+2 
+2 
+2 
+5 
+5 
+5 
+5 
Informed 
consent 
— 
X 
Demographic 
characteristics 
— 
X 
Height 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm 
tuberculosis 
test 
— 
Xf 
Chest x-ray 
— 
Xg 
Electrocardiogra
m (ECG) 
— 
Xr 
Echo cardiogram — 
Xr 
Review 
inclusion/ 
— 
X 

 
 
exclusion 
criteria 
Medical history — 
X 
Physical 
examination 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary Scores 
— 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Previous 
Therapy 
— 
X 
AGS scale, 
GMFM-88 and 
functional 
neurologic 
testing, 
CLASI 
— 
X 
Xs 
Xs 
Adverse events — 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense 
baricitinibk 
— 
X 
X 
X 
Laboratory 
Hematology 
— 
Xh 
Xj 
X 
X 
X 
X 
X 
X 
Xw 
Xw 
Serum 
chemistryv 
— 
Xh 
Xj 
X 
X 
X 
X 
X 
X 
Xw 
Xw 
Lipid panel 
— 
Xh 
X 
X 
X 
X 
Xw 
Urinalysis 
— 
Xh 
Xj 
X 
X 
X 
X 
X 
X 
Xw 
Xw 
IGF-1x 
— 
X 
X 
X 
Vitamin D 
Xw 
Xw 
Xw 
Xw 
Xw 
HBsAg, HBcAb, 
HBsAb 
— 
Xl 
Hepatitis C 
antibody 
— 
Xl 

 
 
HIV 
Xl 
HSV, EBV, CMV — 
Xl 
Xw 
Xw 
Xw 
Xw 
Xw 
Xw 
Xw 
Xw 
Xw 
Lymphocyte 
testing (T cell 
subset) 
— 
Xh 
X 
X 
X 
IgG 
— 
Xh 
X 
X 
X 
Cystatin C 
Xw 
Xw 
Xw 
Xw 
Xw 
Thyroid 
stimulating 
hormone and T4 
— 
Xf 
Xw 
Xw 
Xw 
Xw 
Xw 
Serum 
pregnancy testm 
— 
Xh 
Urine 
pregnancy testm 
— 
X 
X 
X 
X 
X 
X 
X 
BK virus serumu — 
Xh 
X 
X 
X 
X 
X 
X 
Xw 
Xw 
Serum 
baricitinib 
concentrationn 
— 
X 
X 
X 
X 
X 
X 
X 
Xw 
IFN signaling 
score 
— 
Xt 
X 
X 
X 
X 
X 
X 
X 
Xw 
Xw 
Hand/wrist/finger
s X-raysx 
X 
X 
X 
 
Abbreviations: ET = early termination; HBsAg = hepatitis B surface antigen; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HIV = 
human immunodeficiency virus; SAVI = STING-associated vasculopathy with onset during infancy. 
a. 
Early termination visit is required if early termination occurs. 
b. 
Visits occur at approximately 4-week intervals during Weeks 16 through 52 (including both required and optional visits). 
c. 
Visits occur at approximately 12-week intervals during Weeks 60 through 288. 
d. 
Visit 2 encompasses the initial dosing period and can vary in time depending on whether the patient progresses through the first and second 
dose escalation during this period. Four days is the minimum time. 
e. 
Every effort should be made to schedule patient visits within the allowable visit window; however, if a patient visit is scheduled outside the visit 
window, it will not be considered a protocol violation. 
f. 
If results are available from testing within 1 month, then the patient will not have to be retested.  
g. 
Chest X ray will be performed on a clinical basis and results reviewed during screening. If chest x-ray was not performed clinically within 6 
months prior to the study, it will be performed as part of the research study. 
h. 
If results are available from testing within 1 month or as part of the pre-screening period, then the patient will not have to be retested at Visit 1. 
i. 
At least 2 weeks of diary scores are required prior to beginning investigational product.  

 
 
j. 
Collect prior to each dose escalation. Investigator will review to ensure dose escalation is appropriate. Collect prior to the last dose given at Visit 
2.  
k. 
Drug will be dispensed at visit 2, visit 204, and then every 6 months during onsite visits. However, when traveling to the investigative site is not 
considered safe for the patients due to unforeseeable events (see footnote o), such as public or personal health emergencies, the study drug 
may be dispensed for a longer time. 
l. 
If results are available from testing within the previous 3 months, then the patient will not have to be retested. 
m. For female patients of child-bearing potential: a serum pregnancy test will be performed at Visit 1 and a urine pregnancy test (local laboratory) 
will be performed at Visit 2 to determine study eligibility. At subsequent visits, a urine pregnancy test will be performed. 
n. 
Baricitinib concentration samples will be collected at on-site visits. Samples will be collected after beginning baricitinib therapy and at each dose 
escalation, and may be collected at each study visit for safety monitoring. However, when traveling to the investigative site is not considered safe 
for the patients due to unforeseeable events (see footnote o), such as public or personal health emergencies, baricitinib concentration samples 
will not be collected. 
o. 
These required visits should be performed at the investigative site. However, in some circumstances, unforeseeable events, such as public 
health emergencies, states of emergency related to civil unrest, or weather emergencies, or individual health emergencies (affecting the patient 
or a caregiver), may create situations where it is unsafe for patients and their families to travel to the study site for in person assessments. In that 
case, the visits will be conducted using video operations. The changes from an in person evaluation, including differences to the study outcome 
collection, will be reported as a minor protocol deviation to the IRB at the time of continuing review. 
p. 
These required visits may be performed at the investigative site or as a telephone visit. If a telephone visit is performed, lab samples should be 
obtained locally and the required labs to be reported are: total bilirubin, direct bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), blood urea nitrogen (BUN), creatinine, and all hematology. In addition, physical examination is not needed if a 
telephone visit is performed. 
q. 
Optional visits may be performed at the investigative site or as a telephone visit but will not be considered a protocol violation if not performed. If 
a telephone visit is performed, lab samples should be obtained locally. Optional visits between weeks 60 to 288 would only be performed to 
allow patients to re-align with the initial in-person versus phone visits schedule, in cases where this schedule would be disrupted by an 
unforeseeable event (refer to footnote “o” for examples of such events) to enhance patients safety. For instance, if a patient were not able to 
come on-site for several months or years, an in-person visit may be necessary for the providers to assess the patient in-person.  
r. 
EKG and echocardiogram will be performed on a clinical basis and reviewed during screening. 
s. 
Functional outcome assessments will be conducted at baseline and every six months. 
t. 
Three baseline IFN scores will be collected, each at least 5 days apart and not more than 60 days before start of study medication. 
u. 
Patients will be monitored for BK viremia at baseline, and every six months until they reach two years of age. Over two years of age, complete 
follow-up BK testing will be performed if any of the following is observed: blood in urine (as defined by 5-10 RBCS in HPF), protein in urine 
(positive), decrease in eGFR (30 - <60 mL/min/1.73 m2). Follow- BK testing includes urine and serum BK testing. Abnormal urine results with 
urinary tract infection, in the absence of change in eGFR, do not necessitate BK testing. 
v. 
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. 
w. These labs may be drawn (optional). 
x. 
For bone growth monitoring, IGF-1 will be completed yearly, and hand/wrist/fingers X-rays will be completed at baseline, 6 months, 12 months 
and then every 12 months (not after a bone age demonstrating complete growth). 
 
 
 
 
 

 
 
* Visit schedule will be extended beyond Week 288 to long term follow up if transition to commercial supply is not possible 
for a patient. Visit will then be extended until patient transitions to commercial supply. The same tests and procedures that 
were completed during the study will be continued. Visit numbers will continue per the same numbering logic (232, 233, 
234…).  

 
 
Appendix 3. Dose Escalation Schedule for Patients with eGFR ≥60 mL/min/1.73 m2 or Normal eGFR for Age <24 
Months (see footnote belowc) 
 
If a change in the patient’s weight during the study would place the patient in a different weight range, changes over time are permitted. 
 
 
 
Morning Dose 
Noon Dose 
Afternoon Dose 
Evening Dose 
Total Daily Dose 
Dosing Frequency 
eGFR ≥ 60 mL/min/1.73 m2 
5-< 10 kg 
Initial 
1 mg 
1 mg 
0 mg  
1 mg 
3 mg  
TID  
Escalation 1 
1 mg 
1 mg 
1 mg  
1 mg 
4 mg  
QID 
10-< 20 kg 
Initial 
2 mg 
2 mg 
0 mg  
2 mg 
6 mg  
TID 
Escalation 1 
2 mg 
2 mg 
2 mg 
2 mg 
8 mg 
QID 
20-< 40 kg 
Initial 
3 mg 
─ 
0 mg  
3 mg 
6 mg  
BID  
Escalation 1 
3 mg 
─ 
2 mg 
3 mg 
8 mg 
TID 
≥ 40 kg 
Initial 
4 mg  
─ 
─ 
4 mg  
8 mg  
BID 
Escalation 1 
5 mg  
─ 
─ 
5 mg  
10 mg  
BID 
Escalation 2 
6 mg 
─ 
─ 
6 mg 
12 mg 
BID 
BID = twice daily, eGFR = estimated glomerular filtration rate, QID = 4 times daily, TID = 3 times daily. 
a 
If there was a change in the patient’s weight during the study, this would place the patient in a different weight range. 
b 
Based on adult patient data as there is little data available in pediatric patients. 
c.     For the purposes of this protocol, we will define age based parameters for eGFR as follows: Normal renal function not requiring dose adjustments if: >12 months: At least a GFR of >60 
ml/min/1.73 m2. <12 months: A GFR of >40 ml/min/1.73 m2. Patients will be excluded from enrollment if baseline eGFR was <30 ml/min/1.73 m2  
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. 
The population PK analysis was updated including data from 71 juvenile and adolescent patients with Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature 
(CANDLE), CANDLE related disorders, STING-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS).  The analysis has shown that while kidney function, 
as expressed by estimated GFR, is a statistically significant patient cofactor of the PK characteristics of baricitinib in this multi-disease patient population, the effects of eGFR on the kinetics of 
this patient population were not clinically relevant as they relate to dosing and did not support dose adjustment for patients with eGFR less than 120 mL/min/1.73 m2.   

JAK inhibitor treatment in Aicardi Goutières Syndrome 
 
 
  
Appendix 4. Dose Escalation Schedule for Patients with eGFR 30- <60 mL/min/1.73 m2 or for Age <24 Months 
with abnormal eGFR (see footnote belowc) 
 
If a change in the patient’s weight during the study would place the patient in a different weight range changes over time are permitted. 
 
 
 
 
Morning Dose 
Noon Dose 
Afternoon Dose 
Evening Dose 
Total Daily Dose 
Dosing Frequency 
eGFR 30 - < 60 mL/min/1.73 m2b 
10-< 20 kg 
Initial 
1 mg 
1 mg 
0 mg 
1 mg 
3 mg  
TID  
Escalation 1 
1 mg 
1 mg 
1 mg 
1 mg 
4 mg 
QID 
20-< 40 kg 
Initial 
2 mg 
─ 
─ 
1 mg  
3 mg  
BID  
Escalation 1 
2 mg 
─ 
─ 
2 mg 
4 mg 
BID  
≥ 40 kg 
Initial 
2 mg  
─ 
─ 
2 mg  
 
4 mg  
BID 
Escalation 1 
3 mg 
 
─ 
─ 
3 mg 
 
6 mg 
BID 
BID = twice daily, eGFR = estimated glomerular filtration rate, QID = 4 times daily, TID = 3 times daily. 
a 
If there was a change in the patient’s weight during the study, this would place the patient in a different weight range. 
b 
Based on adult patient data as there is little data available in pediatric patients. 
c.     For the purposes of this protocol, we will define age based parameters for eGFR as follows: Normal renal function not requiring dose adjustments if: >12 months: At least a GFR of >60 
ml/min/1.73 m2. <12 months: A GFR of >40 ml/min/1.73 m2. Patients will be excluded from enrollment if baseline eGFR was <30 ml/min/1.73 m2  
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. 
The population PK analysis was updated including data from 71 juvenile and adolescent patients with Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature 
(CANDLE), CANDLE related disorders, STING-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS).  The analysis has shown that while kidney function, 
as expressed by estimated GFR, is a statistically significant patient cofactor of the PK characteristics of baricitinib in this multi-disease patient population, the effects of eGFR on the kinetics of 
this patient population were not clinically relevant as they relate to dosing and did not support dose adjustment for patients with eGFR less than 120 mL/min/1.73 m2.  
 
 
 

JAK inhibitor treatment in Aicardi Goutières Syndrome 
 
  
Appendix 5: AGS severity scale 
 
 
AGS SEVERITY SCALE
Rater ID
Date of 
score
Subject 
ID
Non-microcephalic (0-1)
Smiling (0-1)
No communication (0)
Vocalizations (cooing, babbling, no words) (1)
Limited communication (2)
Intact communication (>3 word sentences) (3)
Fine motor (0-1)
Head control (0-1)
Sitting (0-1)
Non-mobile (0)
Mobile by rolling/crawling (1)
Mobile with devices (2)
Independently mobile (3)
Total Score
Notes about scoring
0
HC requires sustained and consistent ability to control head (ie no bobble 
in supported seated position
0
Fine motor requires a minimum of self feeding OR pincher grasp
0
Smiling requires consistent social smile
0
Vocalizations requires a minimum of consistent ability to make cooing 
(vowel sounds) or babbling (vowel-consonant sounds) sounds
0
Single words: any purposeful words or signs with occasional use of 2 words 
phrases
0
Mobile by rolling/crawling requires a persistent ability to achieve mobility 
by independent rolling (both directions, goal driven)
0
Mobile with devices (2 hand assist, walker, motorized wheelchair), does 
not include children who need full assistance and support
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

JAK inhibitor treatment in Aicardi Goutières Syndrome 
 
  
 
Appendix 6. Patient Daily Diary for AGS infants 0-6 months 
 

 
 
 
Appendix 7. Patient Daily Diary for AGS > 6 months 
 

 
 
 
Appendix 8. Clinical Laboratory Tests 
 
 
Hematologya,b,c 
Serum Chemistrya,b 
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count (RBC) 
Total bilirubinc 
Mean cell volume (MCV) 
Direct bilirubinc 
Mean cell hemoglobin concentration (MCHC) 
Alkaline phosphatase 
Leukocytes (WBC) 
Alanine aminotransferase (ALT/SGPT)c 
Reticulocyte 
Aspartate aminotransferase (AST/SGOT)c 
Absolute counts of: 
Blood urea nitrogen (BUN)c 
Neutrophils, segmented 
Creatininec 
Neutrophils, juvenile (bands) 
Calcium 
Lymphocytes 
Glucose 
Monocytes 
Albumin 
Eosinophils 
Total protein 
Basophils 
Creatine phosphokinase (CPK) 
Platelets 
Uric acid 
Cell Morphology 
Gamma glutamyl transferase (GGT) 
Lymphocyte subset testing 
Aldolased 
IgG 
INRk 
PTk 
Lipide 
Total cholesterol (TC) 
Low-density lipoprotein (LDL) 
Other Testsa 
High-density lipoprotein (HDL) 
Hepatitis B Surface antigen (HBsAg)g 
Triglycerides 
Anti-Hepatitis B Core antibody (HBcAb)g 
Hepatitis B Surface antibody (HBsAb)g 
Urinalysisa,b,f 
Hepatitis B Virus DNAg 
Color 
Human immunodeficiency virus (HIV)g 
Specific gravity 
Hepatitis C antibodyh 
pH 
Thyroid-stimulating hormone (TSH) 
Protein 
Thyroxine (T4) 
Glucose 
Pregnancy Testing 
Ketones 
QuantiFERON®-TB Goldg,j 
Bilirubin 
Baricitinib serum concentration 
Urobilinogen 
BK virus PCR in plasma 
Blood 
BK virus PCR in urine 
Leukocyte esterase 
EBV PCR in plasma-quantitative 
Nitrite 
CMV PCR in plasma-quantitative 
HSV IgG and IgM 
IGF-1 
Vitamin D 
 
Cystatin C 

 
 
 
Abbreviations: PPD = purified protein derivative; RBC = red blood cells; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; TB = tuberculosis; WBC = 
white blood cells. 
a. Assayed by local clinical laboratory. 
b. Unscheduled blood chemistry, hematology, and urinalysis panels may be performed at the 
discretion of the investigator. 
c. If a telephone visit is performed, lab samples should be obtained locally and the required labs to 
be reported are: total bilirubin, direct bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), blood urea nitrogen (BUN), creatinine, and all hematology as listed 
d. Perform if inflammatory myositis is present. 
e. Lipid profile.   
f. 
Microscopic examination of sediment performed only if abnormalities are noted on the routine 
urinalysis.  
g. Test required at Visit 1 only to determine eligibility of patient for the study. 
h. A positive hepatitis C antibody result will be confirmed with a positive hepatitis C virus result. 
i. 
For all women of childbearing potential, a serum pregnancy test will be performed at Visit 1 and a 
urine pregnancy test (local laboratory) will be performed at Visit 2 to determine study eligibility. At 
subsequent visits, a urine pregnancy test will be performed. 
j. 
The QuantiFERON®-TB Gold test is the preferred alternative to the PPD test for the evaluation of 
TB infection, and it may be used instead of the PPD test and may be read locally. If the 
QuantiFERON®-TB Gold test is indeterminate, 1 retest is allowed. If the retest is indeterminate, 
then the patient is excluded from the study, unless the DSMB rules that the finding is likely related 
to underlying autoimmunity in AGS and not to TB infection. 
k. At baseline only.

 
 
 
Appendix 9. Management of Liver Enzyme Laboratory values  
 
Clinical laboratory investigation is needed for diagnosis and monitoring based of liver 
involvement in AGS. One-third of individuals with AGS have baseline hepatic 
involvement (AST/ALT >3 x ULN and GGT>2.5 ULN). Therefore using the Drug Induced 
Liver Injury Guidance published by the FDA in July 2009 is not applicable. Thus, the 
following liver enzyme laboratory testing monitoring is proposed: 
- Laboratory screening of hepatic function panel and or comprehensive metabolic 
panel (including AST, ALT, total and direct or conjugated bilirubin, ALK, GGT and 
albumin) will be tested according to study schedule.  
- At baseline, Model for End-Stage Liver Disease (MELD) (in individuals >12 years) 
and the Pediatric End-Stage Liver Disease (PELD) tools will be used to assess for 
underlying hepatic dysfunction. Individuals with scores of >15 will prohibit 
enrollment. 
- If an isolated elevation of ALT/AST>1000 U/L is seen, or direct bilirubin elevation 
>3x ULN, this will result in updated calculation of the MELD or PELD as age 
appropriate, and individuals with scores of >15 will be considered for drug tapering 
and cessation as well as referral to a hepatologist. 
- If during study, or prior to enrollment, AST/ALT elevations of >5x ULN are seen, this 
will result in repeating liver enzyme and serum bilirubin tests weekly. Frequency of 
retesting can decrease to once a month or less if abnormalities stabilize or the 
investigational product has been discontinued and the patient is asymptomatic.  
 
In addition, the following assessments will be performed: 
• Obtaining a history of recent concomitant drug use (including 
nonprescription medications and herbal and dietary supplement 
preparations), alcohol use, recreational drug use, and special diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E where clinically 
indicated; repeating EBV and CMV PCR; autoimmune markers; 
nonalcoholic steatohepatitis; and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents (for 
example, occupational or recreational exposure) 
• Consider obtaining gastroenterology or hepatology consultations 
 

 
 
 
 
 
 
  
 
 
 

 
 
 
Appendix 10. Management of Leukocyte associated laboratory testing and IgG 
 
 
Exclusion criteria specific to leukocytes: 
• 
Neutropenia (absolute neutrophil count [ANC] <500 cells/µL)  
• 
CD4 <250 cell/l on lymphocyte subset testing (where Absolute CD4 
count=Absolute CD3/CD4 count=CD3/CD4 count=CD4 count=Absolute 
CD3+CD4+ cells) 
• 
Patients not meeting criteria can follow protocols for further diagnosis and 
management and be reconsidered for enrollment at a later time 
 
Criteria for consideration of drug tapering and discontinuation: 
• 
IF ANC 750<1000, THEN follow CBC Q 2 weeks until ANC≥1000 
• 
IF ANC 500<750, THEN follow CBC weekly until ANC≥1000.  
• 
IF ANC 250<500, repeat within 48h and if persistent, refer to local immunology or 
infectious disease clinical team to start ID ppx (as per flowchart below) and 
consider G-CSF. Repeat weekly thereafter until ANC ≥1000. 
• 
IF ANC <250, repeat within 48h and if persistent, refer to local immunology or 
infectious disease clinical team to start ID ppx (as per flowchart below) and 
consider G-CSF. Repeat weekly thereafter until ANC ≥1000. 
• 
If <250 persists > 7 days, refer to local immunology or infectious disease clinical 
team to start G-CSF and continue to repeat weekly.  
o If <250 persists >14 days after starting G-CSF, decrease dose to next 
dose increment (ie if 2mg tid decrease to 2mg bid) (Appendix 14) and 
continue to repeat weekly. 
o If <250 persists >14 days after starting G-CSF and dose reduction, taper 
to stop baricitinib.  
 
• 
IF ALC 250<500, THEN follow CBC Q 2 weeks until ALC≥500 AND start ID ppx 
(as per flowchart below).  
• 
IF ALC <250, THEN follow CBC weekly until ALC ≥250 AND refer to local 
immunology or infectious disease clinical team to start ID ppx (as per flowchart 
below). 
• 
IF ALC <250 
o If <250 persists > 7 days, repeat 1 week later. 
o If <250 persists >14 days, decrease dose to next dose increment (ie if 
2mg tid decrease to 2mg bid) (Appendix 14) and continue to repeat 7 days 
and 14 days later. 
o If <250 persists >14 days after dose reduction, taper to stop baricitinib. 
 
Management of immunologic abnormalities  
• 
When these immunologic abnormalities occur, clinical management 
recommendations below will be shared with the local team in the form of a letter 

 
 
 
via email or fax, to enable the clinical team caring for the patient to use these 
best practices. 
• 
General recommendations for clinical management of immunologic abnormalities 
are detailed below, however deviations from this approach by the clinician caring 
for the patient, during the clinical care of this individual, will not be considered a 
protocol deviation. The investigative team will retain decision making about drug 
discontinuation based on the above recommendations. 
• 
Specifically, the use of specific prophylactic agents, G-CSF and GM-CSF may be 
at the clinician’s discretion, for example even if the criteria below for neutropenia 
are not met, based on the child’s overall health and any contraindications (renal 
function or other medications for example). 
 
For management of leukocyte laboratory abnormalities
 
Trigger to consider prophylaxis
ANC >1000
JAK inhibitor Rx
ALC < 500 &
CD4 >250 
PJP ppx, CMV 
monitoring, EBV 
monitoring
CD4 <250 
PJP ppx, CMV 
monitoring, EBV 
monitoring
Anti-fungal* and
HSV ppx
ANC <1000
ALC < 500 & 
CD4 >250
PJP ppx, CMV 
monitoring, EBV 
monitoring
Anti-fungal* and
HSV ppx*
CD4 <250 
PJP ppx, CMV 
monitoring, EBV 
monitoring
Anti-fungal* and
HSV ppx*
ANC 500-1000
Consider G-CSF 
AND Follow 
RULES for ANC 
<1000 with 
regard to ALC and 
CD4
ANC < 500
G-CSF 
Anti-fungal* ppx
AND follow RULES 
for ANC <1000 
with regard to 
ALC and CD4
IgG < 400 mg/dL
Check vaccination 
titers
Consider
IVIG or SCIG AND 
follow Rules for 
ANC, ALC, and 
CD4
Second immunosuppressant 
(continue for 4 weeks after end of 
combo tx)
PJP ppx, CMV 
monitoring, EBV 
monitoring
Anti-fungal* and
HSV ppx
Antifungal ppx should be with a drug that covers mold: posaconazole, voriconazole, itraconazole, or caspofungin
PJP ppx: First-line bactrim; Second-line: dapsone, atovaquone, or pentamidine
HSV ppx: acyclovir or valacyclovir
Second immunosuppressant = Prednisone equivalent >=0.3mg/kg/day or Prednisone equivalent >10mg daily OR tacrolimus, sirolimus, cyclosporine, 
cyclophosphamide, mercaptopurine, mycophenolate mofetil, methotrexate (>=30mg/m2/week), a cytokine blocker, or any chemotherapeutic 
Leukocyte and IgG monitoring for 
clinical care

 
 
 
Appendix 11. Management of Anemia  
 
Exclusion criteria specific to anemia: 
• 
Hemoglobin <7 mg/dL (70 g/L) will not be enrolled 
• 
Hemoglobin <8 mg/dl will be used as a threshold in infants <2 months 
• 
Patients not meeting criteria can follow protocols for further diagnosis and 
management and be reconsidered for enrollment at a later time 
 
Criteria for consideration of drug tapering and discontinuation: 
 
• 
Patients who develop a hemoglobin (Hg) of <7gm/dl*, should be transfused 
PRBCS as per institutional practice and a post transfusion Hg be measured 
weekly. 
• 
Patients who develop a hemoglobin (Hg) of <7gm/dl* within <4 weeks of the 
transfusion should taper baricitinib to next dose increment (e.g. 2 mg tid to 2 mg 
bid) and be transfused PRBCS as per institutional practice and a post transfusion 
Hg be measured weekly. 
• 
Patients who develop a hemoglobin (Hg) of <7gm/dl* within <4 weeks of the 
transfusion should taper baricitinib to next dose increment (e.g. 2 mg bid to 1 mg 
bid) and be transfused PRBCS as per institutional practice and a post transfusion 
Hg be measured weekly. 
• 
If hemoglobin (Hg) of <7gm/dl* after two dose reductions, baricitinib should be 
tapered to cessation. 
• 
Patients who develop a hemoglobin <5gm/dl at any time should taper baricitinib 
to cessation and be removed from protocol therapy*. 
• 
Patients may dose escalate in a stepwise fashion after Hg>8gm/dl for >4 weeks. 
 
* if acute blood loss in the context of GI bleeding, surgery, documented immune 
mediated hemolysis or anemia or an accident is the cause of the acute anemia, 
treatment of the underlying cause prior to drug tapering is warranted prior to drug 
tapering. Hemoglobin <8 mg/dl will be used as a threshold in infants <2 months. 
For patients who have been taking baricitinib for > 2 weeks and develop >50% drop in 
hemoglobin from baseline should have following work-up at minimum: CBC, reticulocyte 
count, LDH, haptoglobin, DAT, C5b-9, review of peripheral blood smear. Consider 
consultation with pediatric hematologist. 
 
Management of anemia  
• 
When these hematologic abnormalities occur, clinical management 
recommendations above will be shared with the local team in the form of a letter 
via email or fax, to enable the clinical team caring for the patient to use these 
best practices. The investigative team will retain decision making about drug 
discontinuation based on the above recommendations. 
• 
General recommendations for clinical management of anemia are detailed 
above, however deviations from this approach by the clinician caring for the 
patient, during the clinical care of this individual, will not be considered a protocol 

 
 
 
deviation. An example, would be the use of a transfusion at a level higher than 
the above protocol stipulates, felt to be best taking into consideration the overall 
health of the patient. Specifically, the use of EPO may be at the clinician’s 
discretion. The investigative team will retain decision making about drug 
discontinuation based on the above recommendations. 
 
 
 

 
 
 
Appendix 12. Management of Thrombocytopenia and Thrombocytosis 
 
Exclusion criteria specific to thrombocytopenia/thrombocytosis: 
• 
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.  
• 
Patients not meeting criteria can follow protocols for further diagnosis and 
management and be reconsidered for enrollment at a later time. 
 
Criteria for consideration of drug tapering and discontinuation for 
thrombocytopenia: 
• 
Patients who develop a platelet count of <20,000/ µL ** should be transfused as 
per institutional practice. Platelets should be rechecked weekly. If bleeding 
symptoms occur, platelets should be rechecked sooner. 
• 
Patients who develop a platelet count of <20,000/ µL ** within <4 weeks of 
transfusion should be transfused as per institutional practice and should 
taper baricitinib to next dose increment (e.g. 2 mg tid to 2 mg bid). Platelets 
should be rechecked weekly. If bleeding symptoms occur, platelets should be 
rechecked sooner. 
• 
Patients who develop a platelet count of <20,000/ µL ** after dose reduction 
should be transfused as per institutional practice and should taper baricitinib to 
next dose increment (e.g. 2 mg bid to 1 mg bid). Platelets should be rechecked 
weekly. If bleeding symptoms occur, platelets should be rechecked sooner. 
• 
Patients who develop a platelet count of <20,000/ µL ** after two dose 
reductions, baricitinib should be tapered to cessation. 
• 
Patients who develop a platelet count <10,000/ µL at any time should taper 
baricitinib should be tapered to cessation and permanently discontinued. 
• 
Patients may dose escalate in a stepwise fashion after 4 weeks of stability of 
platelets > 70,000/ µL. 
• 
Patients with a history of non CNS bleeding should taper baricitinib to the next 
dose increment if platelet count falls below 30,000/ µL and be transfused. 
Patients with a history of bleeding or taking anticoagulation cannot be dose 
escalated. If platelet count drops <30,000/ µL at decreased dosing (Appendix 
14), baricitinib should be tapered to cessation and permanently discontinued. 
• 
Patients with a history of CNS bleeding or taking anticoagulation should taper 
baricitinib to the next dose increment (Appendix 14) if platelet count falls below 
50,000/ µL and be transfused. Patients with a history of bleeding or taking 
anticoagulation cannot be dose escalated. If platelet count drops <50,000/ µL at 
decreased dosing (Appendix 14), baricitinib should be tapered to cessation and 
permanently discontinued. 
 
** if documented immune mediated thrombocytopenia is the cause, treatment 
of the underlying cause prior to drug tapering is warranted prior to drug 
tapering. For patients who have been taking baricitinib for > 2 weeks and 
develop >50% drop in platelet count should have following work-up at 

 
 
 
minimum: CBC, reticulocyte count, LDH, haptoglobin, DAT, C5b-9, review of 
peripheral blood smear. Consider consultation with pediatric hematologist. 
 
 
Criteria for consideration of drug tapering and discontinuation for 
thrombocytosis: 
• 
Patients who do not have a known vasculopathy and who develop a platelet 
count of >1,000,000/ µL *** should be rechecked < 1 week. 
• 
If platelets remain >1,000,000/ µL ***, they should taper baricitinib to next dose 
increment (e.g. 2 mg tid to 2 mg bid). Platelets should be rechecked weekly.  
• 
If platelets remain >1,000,000/ µL *** after dose reduction, they should 
taper baricitinib to next dose increment (e.g. 2 mg bid to 1 mg bid). Platelets 
should be rechecked weekly.  
• 
If persistent platelets > 1,000,000/ µL *** after >14 days, should taper baricitinib 
to discontinuation. 
• 
Patients may dose escalate in a stepwise fashion after 4 weeks of stability of 
platelets <800,000/ µL.  
• 
For individuals with known CNS vasculopathy (e.g. prior strokes, moya moya), 
take same measures for platelet counts ≥ 800,000/mcL. 
• 
Consider consultation with pediatric hematologist. 
***Consider if there is an alternative explanation (such as intercurrent illness as platelets 
are an acute phase reactant). 
 
 
Management of Thrombocytopenia and Thrombocytosis 
• 
When these abnormalities occur, clinical management recommendations above 
will be shared with the local team in the form of a letter via email or fax, to enable 
the clinical team caring for the patient to use these best practices 
• 
General recommendations for clinical management of thrombocytopenia and 
thrombocytosis are detailed above, however deviations from this approach by the 
clinician caring for the patient, during the clinical care of this individual, will not be 
considered a protocol deviation. The investigative team will retain decision 
making about drug discontinuation based on the above recommendations. 
 
 
 
 

 
 
 
Appendix 13. Cutaneous LE Disease Area and Severity Index (CLASI) 
 
 
 
 
 

 
 
 
Appendix 14. Dose tapering guidance 
 
The following serves as guidance for dose tapering if necessary due to subject 
tolerance. If dose tapering is conducted for subject preference, dose tapering may occur 
more slowly, as needed for subject tolerance. 
# in two week increment unless resolution of AE requiring tapering 
* smaller dose increments obtained by pill cutter, until small pill size can be provided to 
patient where available 
 
Initial dose 
Dose decrease 
1 # 
Dose decrease 
2 # 
Dose decrease 
3 # 
Dose decrease 
4 # 
Dose decrease 
5 # 
1 mg bid 
1 mg am and 
0.5 mg* pm 
0.5 mg* bid 
0.5 mg am 
stop 
 
1 mg tid 
1 mg bid 
1 mg am and 
0.5 mg* pm 
0.5 mg* bid 
0.5 mg am 
stop 
1 mg qid 
1 mg tid 
1 mg bid 
1 mg am and 
0.5 mg* pm 
0.5 mg* bid 
stop 
2 mg bid 
1 mg tid 
1 mg bid 
1 mg am and 
0.5 mg* pm 
0.5 mg* bid 
stop 
2 mg tid 
2 mg bid 
1 mg * tid 
1 mg * bid 
0.5 mg* bid 
stop 
2 mg qid 
2 mg tid 
2 mg bid 
1 mg * tid 
1 mg* bid 
stop 
3 mg bid 
2 mg bid 
1 mg * tid 
1 mg * bid 
0.5 mg* bid 
stop 
3-2-3 mg 
2 mg tid 
2 mg bid 
1 mg * tid 
1 mg * bid 
stop 
3 mg qid 
3-2-3-2 mg 
2 mg qid 
2-1-2-1 mg  
1 mg qid 
stop 
4 mg bid 
2 mg tid 
2 mg bid 
1 mg * tid 
1 mg* bid 
stop 
4-2-4 mg 
2 mg* qid 
2 mg tid 
2 mg bid 
1 mg bid 
stop 
5 mg bid 
4 mg bid 
2 mg tid 
2 mg bid 
1 mg bid 
stop 
4 mg tid 
2 mg* qid 
2 mg tid 
2 mg bid 
1 mg bid 
stop 
6 mg bid 
5 mg bid 
4 mg bid 
2 mg tid 
2 mg bid 
stop 
 

 
 
 
Appendix 15. Decision tree in case of infection suspicion or confirmation 
 
 
 
 
Is an infection suspected or confirmed? 
Is EBV/CMV reactivation present and felt 
to be secondary to Baricitinib? 
Does the child have evidence of VZV 
infection and felt to be secondary to 
Baricitinib? 
- Consider possible drug decrease if 
advised by local immunology or ID team 
if systemic involvement and re-increase 
when improvement of EBV/CMV PCR 
- SAE notification <24h – notification to 
IRB, with advice of local immunology or 
ID team of plans to continue or change 
study drug 
Yes 
Yes 
No 
STOP DRUG. - Consider resuming 
only when any below criteria met: 
▪ Lesions crusted 
▪ VZV PCR negative 
▪ Significant symptomatic improvement  
- SAE notification <24h – notification to 
IRB with advice of local ID team 
Is the infection complicated/ 
disseminated, as defined per protocol? 
Yes 
Is the child hospitalized or getting IV 
antimicrobials? 
No 
No 
Yes 
SAE notification <24h – notification to 
IRB, with advice of local ID team, of 
plans to continue or change study drug 
No 
Does the child have recent ANC, ALC, 
IgG, lymphocyte subset levels that meet 
monitoring criteria with ongoing 
infection? 
Yes 
SAE notification <24h – notification to 
IRB, with advice of local ID team, of 
plans to continue or change study drug 
 
No additional action taken, treat infection as per clinical standards 
Yes 
No 

 
 
 
Appendix 16. Concomitant medication approach in patients with AGS receiving 
baricitinib 
 
The information below is based on a review of Lexicomp and the published prescribing 
information on April 4, 2020. 
 
1. Permitted 
Permitted medications include any other standard therapy used to manage signs and 
symptoms of AGS that does not interact to any significant extent with baricitinib (see 
sections 2 and 3). These may include, but are not limited to, medications used to 
manage tone, seizure medications, medications to manage reflux and constipation as 
examples. 
 
2. Use with caution 
This section includes medications that interact with baricitinib but are not absolutely 
contraindicated. If a medication may be used, a dosage adjustment of either the study 
drug or the concomitant medication may be warranted. CYP3A4 is identified as the 
main metabolizing enzyme and in vitro studies indicate that baricitinib does not 
significantly inhibit or induce the activity of cytochrome P450 enzymes (CYPs 3A, 1A2, 
2B6, 2C8, 2C9, 2C19, and 2D6) or inhibit transporters Pgp or OATP 1B1. Renal 
elimination is the principal clearance mechanism and baricitinib is identified as a 
substrate of OAT3, Pgp, BCRP and MATE2-K from in vitro studies.  
In the following medications, patients should be monitored for safety parameters after 
initiation, but these are not absolutely contraindicated: 
 
• Chloramphenicol (Ophthalmic) 
• CloZAPine 
• Coccidioides immitis Skin Test 
• Promazine/chlorpromazine 
 
Therapy modification may be necessary in the following medications, including due to 
OAT1/3 metabolism interference: 
• Echinacea: May diminish the therapeutic effect of Immunosuppressants 
• Probenecid 
• Nitisinone 
• Pretomanid 
• Tolvaptan (brand specific- Jynarque) 
 
Of note regarding vaccinations: 
• Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect 
of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. 
Complete all age-appropriate vaccinations at least 2 weeks prior to starting an 
immunosuppressant. If vaccinated during immunosuppressant therapy, 

 
 
 
revaccinate at least 3 months after immunosuppressant discontinuation. Risk D: 
Consider therapy modification 
• Smallpox and Monkeypox Vaccine (Live) may be given if it is the brand vaccine 
Jynneos; this is a live, attenuated, non-replicating vaccine that is effective against 
both smallpox and monkeypox. This excludes the smallpox vaccine which is a 
live replicating vaccine. If this vaccine is given the following should be noted: 
Immunosuppressants may diminish the therapeutic effect of Smallpox and 
Monkeypox Vaccine (Live).  
 
 
Although the following are not absolutely contraindicated in the context of baricitinib 
use, in the context of this trial, if they need to be initiated, baricitinib will be tapered to 
cessation when use is initiated: 
• Azathioprine 
• Cyclosporine is not recommended.  
• Antirheumatic doses of methotrexate   
• Nonbiologic disease modifying antirheumatic drugs (DMARDs) 
• Deferiprone 
• Denosumab 
• Fingolimod 
• Leflunomide 
• Mesalamine 
• Nivolumab 
• Roflumilast 
• Sipuleucel-T 
• Pidotimod 
• Tertomotide 
• Trastuzumab 
 
3. Prohibited 
The following are medications that cannot be administered to a patient enrolled on the 
study under any circumstance: 
 
• BCG (Intravesical).  
• Belimumab 
• Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) 
• Cladribine 
• Dipyrone 
• Natalizumab 
• Pimecrolimus 
• Tacrolimus (Topical) 
• Vaccines (Live) Exceptions: Smallpox and Monkeypox Vaccine (Live) if it is the 
brand vaccine Jynneos.  
 
 

 
 
 
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