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Olumiant® (baricitinib): Förändringar i kreatinfosfokinas i kliniska studier av atopisk dermatit

Förhöjningar i CPK var mestadels asymtomatiska och övergående och var inte associerade med muskelrelaterade symtom. Det fanns inga bekräftade fall av rabdomyolys och inga avbrott i behandlingen på grund av förhöjd CPK.

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Changes in Creatine Phosphokinase Levels in Atopic Dermatitis Clinical Trials

Routine monitoring of CPK is not warranted during treatment with BARI.1

Mean Change From Baseline in Creatine Phosphokinase

The mean change from baseline increases in CPK was observed in the BARI 2 mg and BARI 4 mg groups at week 4 and remained higher than baseline up to week 16 (see Mean Changes in CPK Over Time in Patients Treated With BARI 4 mg and BARI 2 mg in the Extended Dataset in the Atopic Dermatitis Clinical Trials and Mean Change From Baseline of CPK in Atopic Dermatitis Clinical Trials).1

Mean Changes in CPK Over Time in Patients Treated With BARI 4 mg and BARI 2 mg in the Extended Dataset in the Atopic Dermatitis Clinical Trials1

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CPK = creatine phosphokinase; ext = extended.

Mean Change From Baseline of CPK in Atopic Dermatitis Clinical Trials1

 

 

 

 

 

 

 

 

 

 

 

BARI 2 mg Placebo-Controlleda

BARI 4 mg Placebo-Controlleda

BARI 2 mg vs 4 mga

BARI 2 mg vs 4 mg ext

All BARI AD

LSMDb (SE) [95% CI]

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

CPK (U/L)

-7.0 (15.79) [-37.97, 23.96]

36.6 (16.95)[3.39, 69.88]c

1.8 (7.98) [-13.82, 17.51]

35.8 (9.10) [17.99, 53.70]d

40.5 (22.24) [-3.13, 84.16]

28.9 (23.39) [-17.01, 74.77 ]

34.4 (26.74) [-18.06, 86.86]

51.3 (28.11) [-3.86, 106.46]

47.1 (12.42) [22.75, 71.48]

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CPK = creatine phosphokinase; ext = extended; LSMD = least squares mean difference.

aData through 16-week placebo-controlled period.

bFrom last measure during baseline to last observation post baseline.

cp<.05 BARI 2 mg vs placebo.

dp<.01 BARI 4 mg vs placebo.

Treatment-Emergent Elevated Creatine Phosphokinase Values in the Atopic Dermatitis Clinical Trials

Dataset Description

The integrated datasets used to evaluate changes in CPK are described in more detail in Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials.

Common Terminology Criteria for Adverse Events Grades for Elevated Creatine Phosphokinase

Categorical changes in CPK values were assessed by determining the proportion of patients with

  • TE values above the ULN, and
  • TE increases in CTCAE grade for elevated CPK.1

For elevated CPK the CTCAE grading includes

  • grade 0 (normal): ≤ULN
  • grade 1: >ULN and ≤2.5 x ULN
  • grade 2: >2.5 x ULN and ≤5 x ULN
  • grade 3: >5 x ULN and ≤10 x ULN, and
  • grade 4: >10 x ULN.2

Proportions of Patients With Elevated Creatine Phosphokinase Values in Atopic Dermatitis Clinical Trials

The majority of the shifts were to grade 1; in the BARI 2 mg and BARI 4 mg placebo-controlled datasets a shift to grade 1 were significantly different (p<0.05) than placebo. A summary of the CTCAE grade increases for each dataset is provided in Overview of CTCAE Grade Increase in CPK in Atopic Dermatitis Clinical Trials.1

Overview of CTCAE Grade Increase in CPK in Atopic Dermatitis Clinical Trials1,3

 

CTCAE Grade 1+
(>ULN and ≤2.5 x ULN)

CTCAE Grade 2+
(>2.5 x ULN and ≤5 x ULN)

CTCAE Grade 3+
(>5 x ULN and ≤10 x ULN)

CTCAE Grade 4+
(>10 x ULN)  

BARI 2 mg Placebo-Controlleda, n/NAR (%)b

Placebo, n=889

84/783 (10.7)

26/856 (3.0)

16/865 (1.8)

10/869 (1.2)

BARI 2 mg, n=721

125/638 (19.6)c

33/697 (4.7)

16/703 (2.3)

8/706 (1.1)

BARI 4 mg Placebo-Controlleda, n/NAR (%)b

Placebo, n=743

69/667 (10.3)

22/717 (3.1)

14/723 (1.9)

9/727 (1.2)

BARI 4 mg, n=489

106/446 (23.8)d

31/477 (6.5)e

16/487 (3.3)

7/488 (1.4)

BARI 2 vs 4 mga, n/NAR (%)b

BARI 2 mg, n=576

99/513 (19.3)

27/559 (4.8)

14/564 (2.5)

7/567 (1.2)

BARI 4 mg, n=489

106/446 (23.8)

31/477 (6.5)

16/487 (3.3)

7/488 (1.4)

BARI 2 mg vs 4 mg extended, n/NAR (%)b

BARI 2 mg, n=576

134/513 (26.1)

39/559 (7.0)

19/564 (3.4)

10/567 (1.8)

BARI 4 mg, n=489

160/446 (35.9)f

49/477 (10.3)

24 /487 (4.9)

12/488 (2.5)

All BARI AD, n/NAR (%)b

All doses, N=2531 

634/2201 (28.8)

196/2430 (8.1)

95/2471 (3.8)

51/2483 ( 2.1)

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CPK = Creatine Phosphokinase; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number of patients at risk for specified abnormality.

aData through 16-week placebo-controlled period.

b% based on number of patients at risk CPK increase.

cp<.001; Difference between BARI 2 mg and placebo.

dp<.001; Difference between BARI 4 mg and placebo.

ep<.01; Difference between BARI 4 mg and placebo. 

fp<.01; Difference between BARI 2 mg and BARI 4 mg. 

Patients With Creatine Phosphokinase Greater than 5 times the ULN

A post hoc analysis was performed in patients with a CPK >5 x ULN (grade 3 or grade 4) at any point in the All BARI AD dataset. There were 94 patients identified and the characteristics included

  • mean age: 31 years
  • males: 74%
  • dose received: BARI 4-mg (39%), 2-mg (45%), or 1-mg (16%), and
  • race: Caucasian (39%), Asian (32%), Caucasian-Hispanic-Latino (18%), African American (6%), Multiple (4%), and Unknown (1%).1

Of the 94 patients with a CPK >5 × ULN (grade 3 or grade 4)

  • 75.5% had a normal baseline CPK
  • a mean maximum CPK of 5556 U/L, median CPK 2779 U/L, and maximum CPK value of 28540 U/L, and
  • 82% reported strenuous exercise or work.1

The time to onset of CPK >5 x ULN (grade 3 or 4) was a mean of 125 days, a median of 82 days, and a range of 14 to 642 days.

Creatine phosphokinase values returned to baseline in 73% patients, the mean time to return to baseline was 37 days (range of 4 to 126 days).1

Adverse events were reported in 24 patients, and of these

  • 12 were mild
  • 7 were moderate
  • 2 were severe, and
  • 3 cases did not have a severity provided.1

Grade 3 or grade 4 CPK (>5 x ULN) elevation led to

  • interruption of treatment in 2 (2.1%) patients, and
  • discontinuation of treatment in 2 (2.1%) patients.1

Incidence of Muscle-Related Adverse Events in Patients With Creatine Phosphokinase >5 ULN

In patients with a CPK >5 × ULN (grade 3 or grade 4), 5 patients had muscular symptoms including

  • mild myalgia (n=2)
  • diffuse leg pain (n=1)
  • muscular pain (n=1), and
  • sore muscles (n=1).1

In these 5 patients, the muscle symptoms were not associated with rhabdomyolysis.1
A dose related response was not observed.1

Adverse Events Related to Elevated Creatine Phosphokinase in the Atopic Dermatitis Clinical Trials

In the All BARI AD dataset, none of the CPK-related TEAEs were considered serious. The TEAEs led to

  • interruption of treatment in 5 (0.2%) patients, and
  • discontinuation of treatment in 2 (0.1%) patients.1

Evaluation of elevations in CPK in the AD clinical program included a review of TEAEs using a query for “muscle symptoms.” The muscle symptoms query used a sponsor-defined MedDRA search criteria list that contained narrow scope terms from the rhabdomyolysis and myopathy standardized MedDRA query plus selected terms from the Musculoskeletal System Organ Class.1

Treatment Emergent Muscle Symptoms in the All BARI AD Dataset

In patients with AD who received BARI in clinical trials, TE muscle symptoms

  • were reported in 32 out of 2531 patients, and
  • occurred in 1.3% of patients with an incidence rate of 1.4 per 100 PYE.1

In the All BARI AD dataset, treatment emergent muscle symptoms observed included

  • myalgia in 22 (0.9%) patients
  • muscle spasms in 7 (0.3%) patients
  • muscle tightness in 1 (0%) patient
  • myofascial pain syndrome in 1 (0%) patient, and
  • myositis in 1 (0%) patients.1

There were no confirmed cases of rhabdomyolysis.1

Potential Role of Janus Kinase Inhibition In Muscle Metabolism

Increases in CPK have been described in association with JAK inhibitors.4-6

Integrated Safety Datasets Table

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials1,3

Analysis Set

Description

BARI 2 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and BREEZE-AD7

Compares BARI 2 mg vs placebo

Includes patients with AD from 1 phase 2 and 5 phase 3 studies who were randomized to

  • BARI 2 mg (n=721, PYE=210.6), or
  • placebo (n=889, PYE=252.7).

Treatment period was 0 to 16 weeks.

BARI 4 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7

Compares BARI 4 mg vs placebo

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 4 mg (n=489, PYE=147.1), or
  • placebo (n=743, PYE=211.8).

Treatment period was 0 to 16 weeks.

BARI 2 mg vs 4 mg

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7

Compares BARI 2 mg vs BARI 4 mg through 16 weeks

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 2 mg (n=576, PYE=169.1), or
  • BARI 4 mg (n=489, PYE=147.1).

Treated for 0 to 16 weeks during the placebo-controlled period.

BARI 2 mg vs 4 mg Extended

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3

Compares BARI 2 mg vs BARI 4 mg including extended evaluations

Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to

  • BARI 2 mg (n=576, PYE=425.5), or
  • BARI 4 mg (n=489, PYE=459.3).

Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3.

All BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6

No between-group comparisons

Includes 2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including

  • BARI 1 mg (n=538, PYE=245.9)
  • BARI 2 mg (n=1580, PYE=1129.5), and
  • BARI 4 mg (n=914, PYE=872.8).

Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo.

 No censoring of data at dose change.

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

Baricitinib Label Information Related to Creatine Phosphokinase

In rheumatoid arthritis controlled studies, for up to 16 weeks, increases in CPK values were uncommon. Significant increases (> 5 x ULN) occurred in

  • 0.8 % of patients treated with baricitinib and
  • 0.3 % of patients treated with placebo.7

A dose relationship was observed with CPK elevations ≥ 5 x ULN of normal reported in 1.5 %, 0.8 % and 0.6 % of patients at 16 weeks in the 4 mg, 2 mg and placebo groups, respectively.7

In atopic dermatitis controlled studies, for up to 16 weeks, increases in CPK values were common and occurred in 3.3 %, 2.5 %, and 1.9 % of patients treated with baricitinib 4 mg, 2 mg, and placebo, respectively.7

In rheumatoid arthritis and atopic dermatitis clinical trials, there were no confirmed cases of rhabdomyolysis. Elevations of CPK were observed at 4 weeks and remained stable at a higher value than baseline thereafter including in the long-term extension study.7

Across indications, most cases were transient and did not require treatment discontinuation.7

References

1Data on file, Eli Lilly and Company and/or one of its subsidiaries.

2National Institutes of Health (NIH). Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Bethesda, MD: U.S. Department of Health and Human Services; 2010. NIH Publication 09-5410. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf

3Bieber T, Thyssen JP, Reich K, et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur Acad Dermatol Venereol. Published online September 14, 2020. https://doi.org/10.1111/jdv.16948

4Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol. 2019;46(1):7-18. http://dx.doi.org/10.3899/jrheum.171361

5Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open‑label, longterm extension studies. J Rheumatol 2014;41(5):837-852. https://doi.org/10.3899/jrheum.130683

6Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13(4):234-243. http://www.nature.com/nrrheum/journal/v13/n4/full/nrrheum.2017.23.html?foxtrotcallback=true

7Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Glossary

AE = adverse event

BARI = baricitinib

CPK = creatine phosphokinase

CTCAE = Common Terminology Criteria for Adverse Events

JAK = Janus kinase

MedDRA = Medical Dictionary for Regulatory Activities

PYE = patient-years of exposure

TE = treatment-emergent

TEAE = treatment-emergent adverse event

ULN = upper limit of normal

Datum fӧr senaste ӧversyn 2021 M02 02


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