Olumiant® ▼ (baricitinib): Opportunistiska infektioner vid RA

Identification of Potential Opportunistic Infections

Identification of OIs in the clinical trial program employed both a screening and a manual review step.

• The screening step used 2 approaches to select relevant cases: 1 using a prespecified list of MedDRA preferred terms and the other using a prespecified list of infecting organisms and infection sites as reported by the investigator on an infection-specific case report form.

• All events with at least 1 infecting organism were also manually reviewed to identify relevant cases. All relevant cases were subject to detailed review of all available clinical data, including information in the Lilly Safety System that may not be in the clinical trial database.

• Tuberculosis, multidermatomal HZ, and OI events were independently reviewed by 3 external clinicians with infectious disease expertise using previously published OI consensus case definitions.¹

Additional information and details on TB and HZ in the BARI clinical trial program are discussed in separate responses.

Opportunistic Infections in the Baricitinib Rheumatoid Arthritis Clinical Development Program

Integrated datasets used in safety analyses are described in Table 2.

Incidence of Opportunistic Infections

In the All BARI RA dataset, the incidence rate per 100 PYE for OIs including multidermatomal HZ but excluding TB was 0.5 (n=61/3770).²

The majority of the OIs reported for patients in the All BARI RA dataset were

• multidermatomal HZ

• TB, and

• invasive Candida infections.

Other types of reported OIs include case(s) of Pneumocystis jirovecii pneumonia, cytomegalovirus, aspergillus, cryptococcal, histoplasmosis, paracoccidioides, Epstein Barr virus, disseminated herpes simplex, strongyloidiasis, and legionella.³

Incidence rate details of OIs for the All BARI Dataset, along with 4-Study Extended Dataset, and 7-Study Placebo-Controlled Dataset are presented in Table 1.

Table 1. Summary of Opportunistic Infections in Rheumatoid Arthritis Clinical Trials^2-6

	7-Study Placebo-controlled Dataset to Week 24a	7-Study Placebo-controlled Dataset to Week 24a	7-Study Placebo-controlled Dataset to Week 24a	4-Study Extended Datasetb	4-Study Extended Datasetb	All BARI RAc
	Placebo N=1215 (451 PYE) n (IR)	BARI 2 mg N=479 (186 PYE) n (IR)	BARI 4 mg N=1142 (472 PYE) n (IR)	BARI 2 mg N=479 (775 PYE) n (IR)	BARI 4 mg N=479 (781 PYE) n (IR)	Phases 1-3 N=3770 (13,148 PYE) n (IR)
OI including multidermatomal herpes zosterd	2 (0.5)	0	4 (0.9)	2 (0.3)	3 (0.4)	61 (0.5)
OI excluding multidermatomal herpes zostered	1 (0.2)	0	3 (0.7)	2 (0.3)	2 (0.3)	32 (0.2)
Multidermatomal herpes zosterf	1 (0.2)	0	1 (0.2)	0	1 (0.1)	30 (0.2)g
Tuberculosis	0	0	1 (0.2)	0	5 (0.6)	20 (0.2)

Abbreviations: BARI = baricitinib; HZ = herpes zoster; IR = incidence rate per 100 PYE; OI = opportunistic infection; PYE = patient-years exposure; RA = rheumatoid arthritis.

^a The 7-study placebo-controlled dataset includes patients with RA who were randomized to placebo (n=1215), BARI 2 mg (n=479), and BARI 4 mg (n=1142) from 7 phase 2 and 3 trials with data through 24 weeks.

^b The extended dataset included patients with RA randomized to BARI 4 mg or BARI 2 mg from 4 phase 2 and 3 studies and 1 long term extension study. The evaluation time periods included randomization through last available observation incorporating extension data through 01 September 2019. Data was censored at rescue or dose change.

^c The All BARI RA analysis set included 3770 patients with RA who received BARI at a variety of doses from 1 phase 1, 3 phase 2, and 5 phase 3 studies. Data includes a long-term extension study with a maximum exposure of 8.4 years and data through 01 September 2019.

^d Excludes tuberculosis.

^e Includes the following OIs: histoplasmosis, pneumonia cryptococcal, Pneumocystis jirovecii pneumonia, invasive candidiasis, cytomegalovirus infection, Paracoccidioides infection, Aspergillus species infection, Epstein-Barr virus infection, disseminated herpes simplex, strongyloidiasis, legionella.

^f Multidermatomal herpes zoster, as defined by HZ infection distributed beyond primary and adjacent dermatomes.

^g Includes an additional case reported as "disseminated zoster" that was not included in the total opportunistic infection number.

Datasets Used in Integrated Safety Analyses

Table 2. Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials^3,4,7

Analysis Set	Descriptiona
7-Study Placebo-Controlled Dataset Studies: JADC, JADA, JADN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE	Compares BARI 4 mg vs placebo Includes patients with RA from 3 phase 2 and 4 phase 3 studies who were randomized to BARI 4 mg (N=1142, [exposure through 24 weeks: PYE=471.8, median exposure=169 days, maximum exposure=211 days]), or placebo (N=1215, [exposure through 24 weeks: PYE=450.8, median exposure=166 days, maximum exposure=235 days]). Patients in the placebo group could have been taking background MTX, or in some studies, other conventional DMARD therapy. Evaluation time periods included through the 12-week placebo-controlled period in phase 2 studies through 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and through 24 weeks of assigned treatment or until rescue in phase 3 studies. BARI 2 mg Analysis Set BARI 2 mg data is derived from 4 studies in which both BARI 2 mg (N=479, [exposure through 24 weeks: PYE=185.8, median exposure=168 days, maximum exposure=197 days]) and BARI 4 mg were options during randomization (JADA, JADN, RA-BUILD, RA-BEACON).
4-Study Extended Dataset Studies: JADA, JADN, RA-BUILD, RA-BEACON, RA-BEYOND (extension)	Compares BARI 4 mg vs BARI 2 mg including extended evaluations Includes patients with RA from 2 phase 2 and 2 phase 3 studies and any further exposure for those patients in the phase 3 extension study, RA-BEYOND, who were randomized to BARI 4 mg (N=479, PYE=781.1, median exposure=342 days, maximum exposure=3085 days), or BARI 2 mg (N=479, PYE=774.9, median exposure=257 days, maximum exposure=2370 days). Evaluation time period included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified.
All BARI RA Dataset Studies: JADB, JADC, JADA, JADN, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE, RA-BEYOND (extension)	No between-group comparisons Includes patients with RA (N=3770, PYE=13,148, median exposure=4.2 yrs, maximum exposure=8.4 yrs) from 1 phase 1, 3 phase 2, 5 phase 3 studies, and 1 phase 3 extension study who received BARI at a variety of doses, including BARI 4 mg (n=3400) BARI 2 mg (n=1077), and BARI 1 mg, 7 mg, 8 mg, and 10 mg QD doses not evaluated in confirmatory studies. Patients had to have received at least 1 dose of BARI and could have received different doses throughout the trials. Evaluation time period is all exposure time points including after rescue or changes in study drug through 01 September 2019 unless otherwise specified.

Abbreviations: BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; PYE = patient-years of exposure; QD = once daily; RA = rheumatoid arthritis.

^a Patients with renal function impairment who were randomized to BARI 4 mg, but treated with the 2-mg dose were analyzed in the BARI 4-mg group.

Special Warnings and Precautions for Use Related to Infections

Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo. In treatment naïve patients, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy.⁸

The risks and benefits of treatment with baricitinib should be carefully considered prior to initiating therapy in patients with active, chronic or recurrent infections.⁸

If an infection develops, the patient should be monitored carefully and baricitinib therapy should be temporarily interrupted if the patient is not responding to standard therapy. Baricitinib treatment should not be resumed until the infection resolves.⁸

Patients should be screened for tuberculosis (TB) before starting baricitinib therapy.⁸

• Baricitinib should not be given to patients with active TB.⁸

• Anti-TB therapy should be considered prior to initiation of Baricitinib in patients with previously untreated latent TB.⁸

References

1. Winthrop KL, Harigai M, Genovese MC, et al. Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Ann Rheum Dis. Published online August 11, 2020. http://dx.doi.org/10.1136/annrheumdis-2019-216852

2. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Poster presented at: European League Against Rheumatism Virtual Congress; June 3-6, 2020.

3. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4. Genovese MC, Smolen JS, Tsutomu T et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol. 2020;2(6):E347-E357. https://doi.org/10.1016/S2665-9913(20)30032-1

5. Chen YH, Chen YM, Smolen J, et al. Incidence rate and characterization of herpes zoster events in patients with moderate to severe rheumatoid arthritis: an update from baricitinib clinical trials. Ann Rheum Dis. 2019;78(2):755. http://dx.doi.org/10.1136/annrheumdis-2019-eular.1130.

6. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 7 years: an updated integrated safety analysis. Presented as an oral presentation at: European League Against Rheumatism (EULAR) Annual Meeting; June 12-15, 2019; Madrid, Spain.

7. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis [abstract]. Ann Rheum Dis. 2020;79(suppl 1):638. http://scientific.sparx-ip.net/archiveeular/?c=a&view=4&item=2020FRI0123

8. Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Glossary

BARI = baricitinib

HZ = herpes zoster

Lilly = Eli Lilly and Company

MedDRA = Medical Dictionary for Regulatory Activities

OI = opportunistic infection

PYE = patient-years of exposure

RA = rheumatoid arthritis

TB = tuberculosis

TEAE = treatment-emergent adverse event

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.