Background: There are no treatments approved by the Food and Drug Administration for alopecia areata. Objective: To evaluate the efficacy and safety of baricitinib in patients with $50% scalp hair loss in a phase 2 study of adults with alopecia areata (BRAVE AA1). Methods: Patients were randomized 1:1:1:1 to receive placebo or baricitinib 1 mg, 2mg, or 4 mg once daily. Two consecutive interim analyses were performed after all patients completed weeks 12 and 36 or had discontinued treatment prior to these time points. The primary endpoint was the proportion of patients achieving a Severity of Alopecia Tool (SALT) score #20 at week 36. Logistic regression was used with nonresponder imputation for missing data. Results: A total of 110 patients were randomized (placebo, 28; baricitinib 1-mg, 28; 2-mg, 27; 4-mg, 27). The baricitinib 1-mg dose was dropped after the first interim analysis based on lower SALT30 response rate. At week 36, the proportion of patients achieving a SALT score of #20 was significantly greater in baricitinib 2-mg (33.3%, P = .016) and 4-mg (51.9%, P = .001) groups versus placebo (3.6%). Baricitinib was well tolerated with no new safety findings.

1. Journal of the American Academy of Dermatology
Published online- June 16, 2021.
ClinicalTrials.gov Identifier: NCT03570749
https://doi.org/10.1016/j.jaad.2021.05.050
Journal Metrics
Impact Factor (2021): 11.53
Indexing: SCOPUS, Science Citation Index, CAB Direct, Embase, Essential Science Indicators, MEDLINE
By: Joel M. Johns, V Pharm.D

2. Funding/Collaborations:
● This Study was funded by Eli Lilly and Company.
● Writing assistance was provided by Manju Janardhanan, MD and Amy Ellinwood,
PhD of Eli Lilly and Company.

3. Introduction
● Alopecia is a widely used term describe hair loss.
● They are broadly classified as
○ Non- Scarring and,
○ Scarring.
● Non- Scarring Alopecia includes- Alopecia Areata, Androgenetic Alopecia etc.
● Scarring Alopecia includes- Central Centrifugal Cicatricial Alopecia, Frontal
Fibrosing Alopecia etc.
● Alopecia areata (AA) is an autoimmune condition characterized by inflammatory,
non-scarring hair loss that has a significant impact on quality of life.
● Although, scalp is majorly affected, it can involve other hair-bearing areas of the
body.

4. Pathophysiology of Alopecia Areata
Autoimmunity
Infiltration by CD8+ natural killer
group 2D T cells and CD4+ T cells
CD8+ cells
Secretion of interferon γ
Signals through JAK1 and JAK3 in T cells
Hair Follicle damage
and Hair Loss
Secretion of interleukin 15
Signals through Janus kinase (JAK)-1 and
JAK2 in the hair follicle epithelial cells

5. Background of the Study
There are no treatments approved by the Food and Drug Administration for alopecia
areata.
Traditional treatment strategies include- steroids, topical immunotherapy, topical
minoxidil, anthralin, and immunosuppressants which is individualized.
To obviate unwarranted side effects of long-term steroid use, immunosuppressant of
relatively safer therapeutic profile can be used.

6. Research Question
Participants Patients with AA
Intervention Baricitinib
Comparator Placebo
Outcomes SALT Score <20
Time (Duration of Study) 36 weeks

7. Objective of the Study
Evaluate the efficacy and safety of baricitinib, a Janus Kinase Inhibitor, in patients
with >50% scalp hair loss in a phase 2 study of adults with alopecia areata

8. Methodology
Study Design- Multi National, Multi-centered, double-blind, placebo (PBO) controlled
study.
Phase II
Participants randomized 1:1:1:1 to receive
once-daily PBO or baricitinib 1-mg, 2-mg, or 4-mg
1st Interim Analysis
Phase III

9. Methodology
● Participants and site personnel remained blinded to treatment allocations.
● Written informed consent was provided by all participants.
● Study protocol was approved by ethical review boards at each site.
● This study was conducted in accordance with-
○ Consensus ethics principles from international ethics guidelines,
○ Declaration of Helsinki and Council for International Organizations of Medical
Sciences
○ International Ethical Guidelines,
○ International Council for Harmonization, and other applicable laws

10. Study Participants- Inclusion Criteria
● 18-60 years at the time of consent.
● Can read, understand, and give documented informed consent
● Current alopecia areata (AA) episode of more than 6 months duration and hair
loss encompassing ≥50% of the scalp, as measured by Severity of Alopecia Tool
(SALT) score at screening and baseline
● No spontaneous improvement (≤10 point spontaneous reduction in SALT) over
the past 6 months

11. Study Participants- Inclusion Criteria
● Current episode of <8 years. For current episode ≥8 years patients may be
enrolled if episodes of regrowth have been observed on the affected areas of the
scalp over the past 8 years.
● Agree not to use any AA treatments during the study (exception: chronic
treatment with bimatoprost ophthalmic solution for eyelashes and chronic
treatment with 5 alpha reductase inhibitors, oral or topical minoxidil)

12. Study Participants- Exclusion Criteria
● Currently experiencing “diffuse” type of AA or other forms of alopecia.
● Have insufficient wash-out of previous AA therapies
● Have a history of inadequate response to an oral Janus Kinase (JAK) inhibitor (for
example, absence of significant terminal hair growth after ≥12 weeks of
treatment.
● Have been exposed to a live vaccine within 12 weeks prior to planned
randomization or are expected to need/receive a live vaccine during the study.

13. Study Participants- Exclusion Criteria
● Having a history of or presence of chronic or unstable illness that, in the opinion
of the investigator, could constitute an unacceptable risk when taking IP or
interfere with the interpretation of data.

14. Study Participants- Exclusion Criteria
● Have a history of eczema herpeticum within 12 months prior to screening or a
history of 2 or more episodes of eczema herpeticum in the past.
● Alcohol or intravenous drug abuse.
● Already enrolled in another clinical study.
● Have participated within last 30 days in a clinical study involving an IP.

15. Methodology
SALT Score-
It is defined as the weighted sum of percent hair loss in the 4 areas of the scalp, was
used to assess the amount of hair loss that involved the scalp.

16. Methodology- SALT Scoring
Assessment tools offer ways to evaluate AA severity [Internet]. Assessing The Severity Of Alopecia Areata (AA). [cited
2023Mar23]. Available from: https://www.understandalopeciaareata.com/assessing-severity

17. Methodology- SALT Scoring
Assessment tools offer ways to evaluate AA severity [Internet]. Assessing The Severity Of Alopecia Areata (AA). [cited
2023Mar23]. Available from: https://www.understandalopeciaareata.com/assessing-severity

18. Methodology- 1st interim analysis
● 1st interim analysis was done to patients who at least completed 12 weeks of
treatment.
● The objective of 1st interim analysis was to identify 2 doses of baricitinib to
advance into second phase of trial.
● Since some patients completed 16 weeks of treatment after at the time of 1st
interim analysis, available week 16 data was also included in dose decision
analysis.

19. Methodology- 1st interim analysis
● The dose decision after 1st interim analysis was based on proportion of patients
achieving > 30% from baseline in SALT score to week 12 and for those with week
16 data, proportion of patients with > 50% improvement from baseline in SALT
score at week 16.

20. Methodology- 2nd interim analysis
Second interim analysis was done to assess the safety and efficacy after all
participants completed 36 weeks of treatment.
Primary End Point Secondary End Points
Proportion of patients achieving a SALT score
<20, previously reported as clinically meaningful
treatment outcome for participants with baseline
score >50.
Percent change from baseline in SALT score
Proportion of participants achieving SALT50
>75% and >90% improvement from baseline
SALT score (SALT75 and SALT90)
Absolute SALT score <10.
Patient reported outcome for Scalp Hair
Assessment score of 0 or 1.
Clinician reported outcome (ClinRO) measures for
eyebrows and eyelashes of 0 or 1 for patients with
PRO/ClinRO measures of eyebrow >2 at baseline
for eyebrow and eyelashes

21. Methodology- 2nd interim analysis
Safety assessments included-
• Periodically assessed symptom-directed physical examination, clinical laboratory
tests, and vital signs.
• Treatment emergent adverse events and other serious adverse events.

22. Methodology- Statistical Analysis
Discontinued participants were considered as non- responders.
Measures Statistical Test Factors
Discrete Efficacy Outcomes
Logistic regression with
geographic region
Duration of current episode at
baseline (<4 years vs >4 years).
Baseline Value.
Treatment Groups.
Continuous Efficacy Outcomes
Analysis of Co-variance (ANCOVA)
with geographic region
Duration of current episode at
baseline (<4 years vs >4 years).
Baseline Value.
Treatment Groups.
Non-responder imputation and modified last observation carried forward were
applied to missing categorical and continuous data, respectively

23. Methodology- Statistical Analysis
● All tests for treatment effects were conducted at 2-sided α level of 0.05 and were
not adjusted for multiplicity.
● Safety analysis included all randomized patients who received > 1 dose of
investigational product and who did not discontinue at the first post-baseline visit
due to lost to follow-up.

24. Results
110 Study
Participants
28
Placebo
28
Baricitinib 1mg
27
Baricitinib 2mg
27
Baricitinib 4mg

25. Baseline Characteristics – Phase II Group

26. Results- 1st interim analysis
● At week 12, SALT30 response was observed in higher proportions in baricitinib
○ 4mg (33.3%),
○ 2mg (29.6%),
○ than those treated with 1mg (17.9%) and PBO (10.7%).
● Among 87 patients who had already completed 16 weeks of treatment or
discontinued, proportion of SALT50 observed were-
○ 38.1% of 4mg treated patients,
○ 31.8% of 2mg treated patients and,
○ 18.2% in 1mg group and 4.5% in PBO group.

27. Results- 1st interim analysis
Thus, 2mg and 4mg were selected for Phase 3 studies.
Participants who were initially assigned to 1mg baricitinib were transitioned to 4mg
and their data was not included at 2nd interim analysis

28. Results- 2nd interim analysis
Primary Outcome:
At week 36, the proportion of patients achieving a SALT score < 20 was significantly
higher in 4mg (51.9%, p= 0.001), 2mg (33.33%, p= 0.016) and PBO (3.6%).

29. Results- 2nd interim analysis
● At week 36, the percent change from baseline in SALT score was significantly
greater with baricitinib 2-mg (-48.2 + 7.9, P<.001) and 4-mg (-58.1 + 7.8,
P<0.0001) compared with PBO (-11.7 + 7.8).
● At week 36, the proportion of patients achieving a SALT score <10
● was significantly greater with baricitinib 2-mg (25.9%, P = .046) and 4-mg
(40.7%, P = .008) versus PBO (0%)

30. Results- 2nd interim analysis
SALT Score
Outcomes PBO
(n=28)
BARI 2mg
(n=27)
BARI 4mg
(n=27)
Proportion of patients achieving
SALT50 (%)
3.6 48.2 (<0.01) 66.7 (<0.001)
Proportion of patients achieving
SALT75 (%)
3.6 29.6 (<0.05) 48.1 (<0.01)
Proportion of patients achieving
SALT90 (%)
0 18.5 40.7 (<0.01)
Proportion of patients achieving
SALT100 (%)
0 11.1 25.9 (<0.05)

31. Results- 2nd interim analysis

32. Results- 2nd interim analysis
ClinRO Measures of Scalp, Eyebrow, and Eyelash Hair Loss.
Outcomes
PBO
(n=28)
BARI 2mg
(n=27)
BARI 4mg
(n=27)
Proportion of patients achieving ClinRO Measure for
Eyebrow Hair Loss scores of 0 or 1
4.3%
28.6%
(0.034)
39.1%
(0.012)
Proportion of patients achieving a ClinRO Measure for
Eyelash Hair Loss score of 0 or 1
5.9% 40% (0.041) 60% (0.041)

33. Results- 2nd interim analysis
PRO Measures of Scalp, Eyebrow, and Eyelash hair loss
Outcomes
PBO
(n=28)
BARI 2mg
(n=27)
BARI 4mg
(n=27)
Proportion of patients achieving PRO measure for Scalp
Hair Assessment score of 0 or 1
3.6%
33.3%
(0.015)
37% (0.07)
Proportion of patients achieving PRO measure for
Eyebrow score of 0 or 1
0 40% (0.015) 45.8% (0.01)
Proportion of patients achieving PRO measure for
Eyelash score of 0 or 1
0 27.8%
57.9%
(0.016)

34. Results- 2nd interim analysis

35. Discussion
● This study is the first randomized clinical trial of baricitinib in patients with AA.
● In phase 2 at week 12, both baricitinib 2-mg and 4-mg demonstrated benefit over
the 1-mg dose and PBO, supporting further evaluation of baricitinib 2mg and 4mg.
● At week 36, a third of the patients taking baricitinib 2-mg and half of the patients
taking baricitinib 4-mg achieved a SALT score <20 compared with PBO (3.6%).
● These results confirm the potential of JAK inhibitors for the treatment of AA.

36. Discussion
● Eyebrow and eyelash responses to baricitinib treatment were notable (in addition
to significant scalp hair regrowth).
● Eyebrow and eyelash regrowth also was observed over 36 weeks of treatment,
with about 30% to 40% of patients with ClinRO Measure for Eyebrow >2 and 40%
to 60% of patients with ClinRO Measure for Eyelash >2 reaching scores of 0
(normal eyebrows/eyelashes) or 1 (minimal gaps).

37. Discussion
● Overall, baricitinib was well tolerated and there were no serious adverse events,
deaths, thromboembolic events, or new safety findings.
● Rates of treatment-emergent adverse events were consistent with expectations,
given an observation period of up to 52 weeks, and were comparable between the
groups.
● Upper respiratory tract infections were the most reported AE.
● Some laboratory abnormalities were observed but these were not associated with
AEs.

38. Study Limitations
● Small sample size.
● The exclusion of patients who previously failed JAK inhibitors could potentially
inflate efficacy estimates; however, the number of patients excluded on this
criterion would likely be small.

39. Conclusions
● The results from the interim analysis suggests that once-daily baricitinib is
effective for patients with >50% scalp hair loss and supports the rationale for the
phase 3 program currently underway.
● Phase 3 of this study is still in progress and is expected to conclude by May-June
2024.

40. CRITIQUE
Consolidated Standards of Reporting Trials (CONSORT)- 2010

41. CONSORT-2010
Section/Topic Checklist Item
Title and Abstract
Identification as a randomized trial in the title ✓
Structured summary of trial design, methods, results,
and conclusions
✓
INTRODUCTION
Background and Objectives
Scientific background and explanation of rationale ✓
Specific objectives or hypotheses ✓
METHODOLOGY
Trial Design
Trial Design and Allocation Ratio ✓
Changes to Methods after trial commencement No changes
Participants
Eligibility Criteria ✓
Settings and locations where the data were collected X

42. CONSORT-2010
Section/Topic Checklist Item
Interventions
The interventions for each group with sufficient
details to allow replication, including how and when
they were actually administered
✓
Outcomes
Completely defined pre-specified primary and
secondary outcome measures, including how and
when they were assessed
✓
Any changes to trial outcomes after the trial
commenced, with reasons
No Changes
Sample Size
How Sample Size was determined? X
When applicable, explanation of any interim analyses
and stopping guidelines
✓
Randomization- Sequence
Generation
Method used to generate the random allocation
sequence
X
Type of randomization ✓

43. CONSORT-2010
Section/Topic Checklist Item
Allocation Concealment
Mechanism used to implement the random allocation
sequence (such as sequentially numbered containers),
describing any steps taken to conceal the sequence until
interventions were assigned
X
Implementation
Who generated the random allocation sequence, who
enrolled participants, and who assigned participants to
interventions
X
Blinding
If done, who was blinded after assignment to
interventions and how?
✓
Statistical Methods
Statistical methods used to compare groups for primary
and secondary outcomes
✓
Methods for additional analyses, such as subgroup
analyses and adjusted analyses
No

44. CONSORT-2010
Section/Topic Checklist Item
RESULTS
Participant flow
For each group, the numbers of participants who were
randomly assigned, received intended treatment, and
were analyzed for the primary outcome
✓
For each group, losses and exclusions after
randomization, together with reasons
✓
Recruitment
Dates defining the periods of recruitment and follow-up X
Why the trial ended or was stopped Ongoing
Baseline data
A table showing baseline demographic and clinical
characteristics for each group
✓
Numbers analysed
For each group, number of participants (denominator)
included in each analysis and whether the analysis was
by original assigned groups
✓

45. CONSORT-2010
Section/Topic Checklist Item
RESULTS
Outcomes and
estimation
For each primary and secondary outcome, results for each
group, and the estimated effect size and its precision
(such as 95% confidence interval)
✓
For binary outcomes, presentation of both absolute and
relative effect sizes is recommended
✓
Ancillary analyses
Results of any other analyses performed, including
subgroup analyses and adjusted analyses, distinguishing
pre-specified from exploratory
No ancillary
analysis
Harms All important harms or unintended effects in each group ✓

46. CONSORT-2010
Section/Topic Checklist Item
DISCUSSION
Limitations
Trial limitations, addressing sources of potential bias,
imprecision, and, if relevant, multiplicity of analyses ✓
Generalizability Generalizability of trial findings No
Interpretation
Interpretation consistent with results, balancing benefits
and harms, and considering other relevant evidence
✓
OTHER INFORMATIONS
Registration Registration number and name of trial registry ✓
Protocol Where the full trial protocol can be accessed, if available X
Funding
Sources of funding and other support (such as supply of
drugs), role of funders
✓

47. Thank You!