Olumiant® ▼ (baricitinib): Renal-Related Adverse Events and Analyte Changes in Atopic Dermatitis

Baricitinib Label Information Related to Renal Impairment and Creatinine

Dosing Recommendations in Renal Impairment

Renal function was found to significantly affect baricitinib exposure.¹

The recommended dose is 2 mg once daily in patients with creatinine clearance between 30 and 60 mL/min. Baricitinib is not recommended for use in patients with creatinine clearance < 30 mL/min.¹

Creatinine

In rheumatoid arthritis, baricitinib induced a mean increase in serum creatinine levels of 3.8 µmol/L after two weeks of treatment, as compared to placebo, which remained stable thereafter during up to 104 weeks of treatment. This may be due to inhibition of creatinine secretion by baricitinib in the renal tubules.¹

Consequently, estimates of the glomerular filtration rate based on serum creatinine may be slightly reduced, without actual loss of renal function or the occurrence of renal adverse events.¹

In atopic dermatitis, baricitinib was associated with a decrease in cystatin C (also used to estimate glomerular filtration rate) of 0.1 mg/L at week 4, with no further decrease noted up to week 16.¹

Renal Impairment in Atopic Dermatitis Clinical Trials

Dose Adjustments for Renal Impairment

In the BREEZE-AD clinical trial program, slight dose-dependent increases in serum creatinine were observed with baricitinib. These were not associated with increased risk of serious renal related AEs such as renal impairment/injury or renal failure.²

In the AD phase 3 studies with the highest dose of 4 mg, patients with an eGFR ≥40 and <60 mL/min/1.73 m²

• received BARI 2 mg once daily if assigned to either the BARI 2 mg or BARI 4 mg treatment arms, and

• received BARI 1 mg if assigned to the BARI 1 mg treatment arm.³

Patients were excluded from these phase 3 studies if they had an eGFR <40 mL/min/1.73 m².³

In the AD phase 3 studies with the highest dose of BARI 2 mg (BREEZE-AD5 and BREEZE-AD6), patients with an eGFR <60 mL/min/1.73 m² were excluded from the studies.³

Estimated GFRs were calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration Creatinine 2009 equation.^3,4

Treatment Interruptions Due to Renal Impairment

In the AD phase 3 clinical trials, routine laboratory monitoring of serum creatinine to calculate eGFR was collected. Clinical trial criteria regarding study treatment interruption based on decreased eGFR are provided in Table 1.³

Table 1. Clinical Trial Criteria for Temporary Interruption and Resumption of Study Treatment Based on eGFR^a in AD Clinical Trials³

Atopic Dermatitis Clinical Trials	Study treatment was interrupted if	Study treatment was resumed when
BREEZE-AD1, BREEZE-AD2, BREEZE-AD3, BREEZE-AD4, and BREEZE-AD7	eGFR decreased to <40 mL/min/1.73 m2 in patients with a screening eGFR ≥60 mL/min/1.73 m2	eGFR increased to ≥50 mL/min/1.73 m2
	eGFR decreased to <30 mL/min/1.73 m2 in patients with a screening eGFR ≥40 to <60 mL/min/1.73 m2	eGFR increased to ≥40 mL/min/1.73 m2
BREEZE-AD5 and BREEZ-AD6	eGFR decreased to <50 mL/min/1.73 m2	eGFR increased to ≥60 mL/min/1.73 m2

Abbreviations: AD = atopic dermatitis; eGFR = estimated glomerular filtration rate.

^a Based on serum creatinine.

Integrated Safety Datasets Used to Evaluate Safety

The integrated datasets used to evaluate safety in the AD clinical trials are described in detail in Table 4

Mean Renal-Related Laboratory Changes

Mean Serum Creatinine Changes

In the AD clinical trial program, minor dose-dependent increases in serum creatinine were observed with BARI treatment; however, the changes were not considered clinically meaningful.²

Mean changes in serum creatinine from baseline to each measurement time point are provided in Figure 1 for the placebo-controlled period and Figure 2 for the BARI 2 mg and 4 mg extended dataset.

Figure 1. Mean Change in Serum Creatinine for AD Placebo-Controlled Datasets³

Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; Max = maximum; Min = minimum; PBO = placebo; PC = placebo-controlled; StdDev = standard deviation.

Figure 2. Mean Change in Serum Creatinine for AD BARI 2 mg vs 4 mg Extended Dataset³

Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; ext = extended; Max = maximum; Min = minimum; StdDev = standard deviation.

Mean Serum Cystatin C Changes

In the AD clinical trial program, there was a mean decrease in serum cystatin C in all treatment groups through week 12, with no further decrease through week 16. The mean changes were not associated with AEs of renal dysfunction.^2,3

Mean changes in serum cystatin C from baseline to each measurement time point are provided in Figure 3 for the placebo-controlled period and Figure 4 for the BARI 2 mg and 4 mg extended dataset.

Figure 3. Mean Change in Serum Cystatin C for AD Placebo-Controlled Dataset³

Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib;  Max = maximum; Min = minimum; PBO = placebo; PC = placebo-controlled; StdDev = standard deviation.

Figure 4. Mean Change in Serum Cystatin C for AD BARI 2 mg vs 4 mg Extended Dataset³

Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; ext = extended; Max = maximum; Min = minimum; StdDev = standard deviation.

Renal Related Laboratory Adverse Events

CTCAE Grade Shifts in Creatinine

Categorical changes in creatinine values were assessed by determining the proportion of patients with a TE value above the ULN as well as the proportion of patients with a TE increase in CTCAE grades. Normal limits were defined according to

• laboratory methodology

• age, and

• sex.³

CTCAE grade shifts are defined as:

• Grade 0: (normal): ≤ULN

• Grade 1: >ULN and ≤1.5 × ULN

• Grade 2: >1.5 × ULN and ≤3 × ULN

• Grade 3: >3 × ULN and ≤6 × ULN, and

• Grade 4: >6 × ULN³

Through 16 weeks, a significantly higher proportion of patients had an increase in any CTCAE grade shift in creatinine in the

• BARI 2 mg group than placebo group (6.2% vs 3.6%; p≤.01)

• BARI 4 mg group than placebo group (8.4% vs 3.6%; p≤.001), and

• BARI 4 mg group than BARI 2 mg group (8.4% vs 5.3%; p≤.05).

The majority of the shifts in all treatment groups were to Grade 1.³ See Table 2 for more details.

Table 2. CTCAE Grade Changes in Creatinine (umol/L)³

	Any Grade Increase	Increased to Grade ≥1	Increased to Grade ≥2	Increased to Grade ≥3	Increased to Grade ≥4
BARI 2 mg placebo-controlleda, n/NAR (%)
Placebo, n=889	31/871 (3.6)	31/821 (3.8)	1/870 (0.1)	1/871 (0.1)	0/871
BARI 2 mg, n=721	44/709 (6.2)b	42/661 (6.4)b	3/708 (0.4)	0/709	0/709
BARI 4 mg placebo-controlleda, n /NAR (%)
Placebo, n=743	26/729 (3.6)	26/693 (3.8)	1/728 (0.1)	1/729 (0.1)	0/729
BARI 4 mg, n=489	41/488 (8.4)c	40/468 (8.5)c	1/488 (0.2)	0/488	0/488
BARI 2 mg vs 4 mga, n/NAR (%)
BARI 2 mg, n=576	30/570 (5.3)	30/538 (5.6)	1/569 (0.2)	0/570	0/570
BARI 4 mg, n=489	41/488 (8.4)d	40/468 (8.5)	1/488 (0.2)	0/488	0/488
BARI 2 mg vs 4 mg extended, n/NAR (%)
BARI 2 mg, n=576	53/570 (9.3)	53/538 (9.9)	2/569 (0.4)	0/570	0/570
BARI 4 mg, n=489	56/488 (11.5)	55/468 (11.8)	1/488 (0.2)	0/488	0/488
All BARI AD, n/NAR (%)
All doses, N=2531	246/2497 (9.9)	240/2312 (10.4)	9/2495 (0.4)	1/2497 (0.0)	1/2497 (0.0)

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number at risk.

^a Data through 16-week placebo-controlled period.

^b p≤.01 vs placebo.

^c p≤.001 vs placebo.

^d p≤.05 vs BARI 2 mg.

Abnormal High Laboratory Results

High Serum Creatinine

A high serum creatinine was defined as above the defined reference range by age and sex.³

Through 16 weeks, compared to placebo, a significantly higher proportion of patients had a TE high serum creatinine in the

• BARI 2 mg group (6.4% vs 3.8%; p≤.01), and

• BARI 4 mg group (8.5% vs 3.8%; p≤.001).³

There was no significant difference in high serum creatinine between BARI 2 mg and BARI 4 mg groups through 16 weeks and extended treatment.³

High Serum Cystatin C

A high serum cystatin C was defined as above the defined reference range by age and sex.³

Through 16 weeks, TE high serum cystatin C was

• significantly lower in the BARI 2 mg group than placebo (2.9% vs 7.9%; p≤.001), and

• not different in the BARI 4 mg group and placebo group (4.5% vs 8.3%).³

There was no significant difference in high serum cystatin C between BARI 2 mg and BARI 4 mg groups through 16 weeks and extended treatment.³

Renal-Related Adverse Events

Of the 2531 patients treated with BARI, renal-related TEAEs were reported in 39 (1.5%, IR=1.7) patients. Events of most interest included

• 4 (IR=0.2) cases of renal impairment

• 3 (IR=0.1) cases of acute kidney injury, and

• 1 (IR=0.0) case of renal failure.³

Of these 8 events, most were considered mild or moderate in severity after medical review, and 5 were not considered related to study drug.³

Table 3 provides more details on renal-related TEAEs by safety dataset and treatment arms.

Table 3. Renal-Related Treatment Emergent Adverse Events³

	BARI 2 mg Placebo-Controlleda n (adj %)b		BARI 4 mg Placebo-Controlleda n (adj %)b		BARI 2 mg vs 4 mga n (adj %)b		BARI 2 mg vs 4 mg ext n (adj %)b [adj IR]		All BARI AD n (%) [IR]
	Placebo n=889	BARI 2 mg n=721	Placebo n=743	BARI 4 mg n=489	BARI 2 mg n=576	BARI 4 mg n=489	BARI 2 mg n=576	BARI 4 mg n=489	All Doses N=2531
Renal and urinary disorders SOC	4 (0.6)	3 (0.3)	3 (0.5)	9 (1.7)c	2 (0.2)	9 (1.7)d	9 (1.4) [2.1]	12 (2.2) [2.6]	39 (1.5 ) [1.7]
Serious AE	0	0	0	0	0	0	0	0	2 (0.1) [0.1]e
Led to temp int	0	0	0	1 (0.2)	0	1 (0.2)	0	1 (0.2) [0.2]	2 (0.1) [0.1]
Led to perm D/C	0	0	0	1 (0.2)	0	1 (0.2)	0	1 (0.2) [0.2]	1 (0.0) [0.0]

Abbreviations: AD = atopic dermatitis; adj = adjusted; AE = adverse event; BARI = baricitinib; ext = extended; IR = incidence rate; perm D/C = permanent discontinuation; SOC = system organ class; temp int = temporary interruption.

^a Data through 16-week placebo-controlled period.

^b For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups. 

^c p≤.05 vs placebo.

^d p≤.05 vs BARI 2 mg.

^e Includes 1 patient with 2 events (calculus urinary and renal colic) and 1 patient with 1 event (renal failure).