JOURNAL CLUB

กลุม A2
กรกนก วัฒนา 5810712004
กัญนิญา ชินวงศเวท 5810712005
กาญจนา มวงทอง 5810712006
 CONTENTS

01 Literature
- Introduction
- Objective
- Method
- Result
- Discussion
- Conclusion

02 Literature evaluation;
Critical Appraisal Skills
Programme (CASP)
Literature
2008

3
 Literature Introduction

- Golimumab, a human monoclonal antibody

to tumour necrosis factor (TNF)-α
- Administered subcutaneously every 4 weeks
- Approved for treating active ankylosing spondylitis (AS).
Golimumab
Golimumab

4
 Literature Objectives

To evaluate the efficacy and safety of golimumab in patients

with ankylosing spondylitis (AS) in the GO-RAISE study.

5
 Literature Method
Study design Randomized, double-blind, placebo-controlled

356 patients, Randomly assigned, in a1:1.8:1.8 ratio

Week 0-24

Placebo Golimumab 50 mg q 4 weeks Golimumab 100 mg q 4 weeks

Placebo Continued Golimumab Continued Continued to 100 mg

Golimumab Placebo 50 mg Golimumab At 24 week
50 mg at at week 24 100 mg 50 mg at
week 16 at week 16 week 16 Evaluated the efficacy
6
and safety of golimumab
 Literature Method
Study agent Randomized, double-blind, placebo-controlled

Placebo
Sterile liquid 0.5 mL Sterile liquid 1.0 mL

Golimumab 50 mg
Golimumab 0.5 mL Sterile liquid 1.0 mL

Golimumab 100 mg
Golimumab 0.5 mL Golimumab 1.0 mL
 Literature Method
Patients

Inclusion Criteria
- Adult patients who had AS (diagnosed modified New York Criteria) for ≥ 3 months
- BASDAI score of ≥ 4
- Spinal pain score of ≥ 4 (visual analog scale)
- Inadequate response or previous NSAIDs drugs or DMARDs
- Normal results of a chest radiograph within 3 months

8
 Literature Method
Patients
Exclusion Criteria
- Ankylosis of the spine
- Others inflammatory rheumatic disease
- Serious infection within 2 months before randomization
- Active or latent TB
- Opportunistic infection
- Hepatitis, human immunodeficiency virus, a transplanted organ,
malignancy, multiple sclerosis, congestive heart failure.

9
 Literature Method
Evaluations
- Primary end point was the proportion of patients with at
least 20% improvement in the ASsessment in AS (ASAS20)
criteria were compared between treatment groups at week 14.
- Secondary end points included
ASAS 40% improvement (ASAS40)
ASAS partial remission
20% improvement in 5 of 6 ASAS domains (ASAS5/6)

10
 Literature Method
Statistical analysis
- Primary and Secondary end points use Cochrane-Mantel-
Haenszel test
- Primary efficacy analysis;
Impute least 1 ASAS component at week 14.
Patients without data for any of the ASAS components
at week 14 Not achieved primary end point.

11
 Literature Method
Statistical analysis
- Logistic regression analysis of the ASAS20 response at week 14
was performed based on the following factors:
Treatment group (placebo or golimumab at either dose),
Screening CRP level (≤1.5 mg/dl or ›1.5 mg/dl)
DMARD use (yes or no)
Continuous variables body weight and duration of AS.

12
Literature Results

Patients
 Baseline patient and
Result disease characteristics
 Result Efficacy

Efficacy

*P 0.001; **P 0.01, versus placebo

ASAS20 response of the primary end point at week 14 :
- 59.4% in the 50 mg group
- 60.0% in the 100 mg group
VS
21.8% in the placebo group (P 0.001)
 Result Efficacy

Sensitivity analysis

Sensitivity analyses indicated the primary end point

Patients who discontinued treatment because of adverse events

Logistic regression

The logistic regression analysis indicated that effects

attributable to treatment group (P 0.001), screening CRP level (P
0.0062), and body weight (P 0.0140) were significantly associated
with ASAS20 responses.
 Result Efficacy
The benefit of golimumab treatment was also consistent across
subgroups of sex, race, age, geographic region, and body weight
except
Patients in the 50-mg group in the weight 87 kg
Patients the 100-mg group in the weight 75.15 kg - ≤87 kg
ASAS20 response was not statistically significantly

The response at week 14

Patients in the combined golimumab group
CRP level >0.6 mg/dl (66.1%) > CRP level ≤ 0.6 mg/dl (49.5)
CRP level >1.5 mg/dl (70.3%) > CRP level ≤1.5 mg/dl (51.9%).
 Result
Result : Efficacy
Efficacy

Greater proportions of patients in the golimumab groups

achieved an ASAS20 response at the first assessment, 4 weeks
after the first injection.
 Result
Result : Efficacy
Efficacy

The mean BASDAI and BASFI scores through week 24

Golimumab groups < Placebo group.
ASAS40 response at week 24 of patients in the 50 mg, 100 mg,
•

and placebo groups

43.5% 54.3% and 15.4%
 Result
Result : Efficacy
Efficacy

At both week 14 and week 24

Patients who received golimumab showed statistically significant
improvements in all components of the ASAS20
 Result
Result : Efficacy
Efficacy

3/5 of the BASMI improved at week 14 or week 24

for golimumab treated patients
Chest expansion at week 24 (significant)
The 50 mg, combined golimumab groups > placebo group
(P 0.013 and P 0.016)
 Golimumab serum
Result concentration.

The time to reach steady state: at week 12

Patients in the 50 mg group (early escape VS not require early escape)
0.36 mg/ ml < 0.59 mg/ml
(median serum golimumab concentrations ) before week 16
The 21 patients (no ASAS20 response) = 4 patients (ASAS20 response)
1.04 mg/ml and 0.90 mg/ml.
Large vari ability in serum golimumab concentrations.
Patients with a heavier body weight tended to have lower serum
golimumab concentrations.
 Antibodies to
Result golimumab.

The incidence was low (4.1%)

The highest titer (1:2,560): In a patient step 50 mg to 100 mg
Antibody positive patients had low serum golimumab
concentrations.
Result Safety (week 16)

≥ 1 adverse event (through week 16)

79.0% in the 50 mg group
75.7% in the 100 mg group
77.3% in the combined golimumab group
74.0% in the placebo group
Serious adverse events (through week 16)
5 (3.6%) in the 50 mg group
7 (5.0%) in the 100 mg group
4 (5.2%) in the placebo group
Result Safety (week 24)
 Result
Result : Safety
Safety
(week 24) 24)
(week

≥ 1 adverse event (through week 24)

3.6% in the 50 mg group
6.4% in the 100 mg group
5.4% in the combined golimumab group
% in the placebo group
1patient in the 50 mg group had MI (day 67)
1 patient in the 100 mg group had severe fatigue,
depression, and hypertension.
No deaths, opportunistic infections, TB.
 Result Safety (week 24)
9 patients discontinued study treatment
2.9% in the 50 mg group
1: increases in liver transaminase levels
1: alcohol withdrawal syndrome, hallucination, and a suicide attempt
1: chest pain
1: blepharitis, nausea, and vomiting
2.9% in the 100 mg group
2: increases in liver transaminase levels
1: hepatitis (noninfectious)
1: depression and hypertension
1.3% in the placebo group
1: headache, influenza-like illness, pain in the extremities, and
increased body weight.
 Result
Result: Safety
Abnormal (week ALT
post base-line 24) or AST values)
Safety (week 24)
**100% increase from baseline and a value >150 IU/liter
9 patients
6/9 continued treatment
2 (50 mg group)
5 (100 mg group)
3/5 discontinued treatment
1 (placebo group)
2 (placebo to 50 mg)
Others
2 patient in the 100 mg group
chronic otitis media, basal cell carcinoma
2 patient in the placebo group
gastrointestinal inflammation, basal cell carcinoma
 Result
Result : Safety
Safety
(week 24) 24)
(week
≥ 1 injection-site reaction (No patients discontinued treatment)
erythema
8.7% in the 50 mg group
6.4% 100 mg group
2.6% in the placebo group
The newly positive test results for antinuclear antibodies (week 14)
No patient had drug-induced lupus.
10 (10.1%) /99 in the 50 mg group
16 (14.8%) /108 in the 100 mg group
1: positive for anti–double-stranded DNA antibodies
8 (12.9%) /62 in the placebo group
 Literature Discussion

Golimumab SC q 4 weeks
- Improve signs and symptoms week 24
- High CRP level group response more than low CRP level
- No differences BASMI scores at week 14 or week 24
- Decrease sleep disturbance
- Serum golimumab concentrations low in positive for
antibodies to golimumab group
- Slightly infections
 Critical
Appraisal Skills
Programme
(CASP)
Section A:

Are the results of the

review valid?
1 Did the trial address a clearly focused issue?

P: ผูaปcวยโรค active AS

I: Golimumab 50 mg or 100 mg

C: Placebo
1 Did the trial address a clearly focused issue?

O:
- Primary end point was the proportion of patients with at
least 20% improvement in the ASsessment in AS (ASAS20)
criteria were compared between treatment groups at week 14.
- Secondary end points included
ASAS 40% improvement (ASAS40)
ASAS partial remission
20% improvement in 5 of 6 ASAS domains (ASAS5/6)
2 Was the assignment of patients to
treatments randomised?

How this was carried out ?

Randomly assigned in a 1.8:1.8:1 ratio

- Receive subcutaneous injections of golimumab
- 50 mg or 100 mg or placebo every 4 weeks

Was the allocation sequence concealed

from researchers and patients ?
ไมไดaระบุถึงการปกปnดลําดับสุม (allocation concealment)
3 Were all of the patients who entered the trial
properly accounted for at its conclusion?

Was the trial stopped early ?

การศึกษาไมไดaหยุดกอนกําหนด

Were patients analysed in the groups to

which they were randomised?

การศึกษานี้ไมไดaระบุถึงการทํา intention-to-treat analysis

3 Were all of the patients who entered the trial
properly accounted for at its conclusion?
4 Were patients, health workers and study
personnel ‘blind’ to treatment?
การศึกษาระบุวา double-blind, randomised, placebo-controlled
Study agent
In the 50 mg group
- Active golimumab in the 0.5 ml syringe
- Placebo in the 1.0 ml syringe
In the 100 mg group
- Active golimumab in the 1.0 ml syringe
- Placebo in the 0.5 ml syringe
In the placebo group
- Placebo in both syringes.
5 Were the groups similar at the start of the trial?

Other factors that might affect the outcome

such as; age, sex, social class ?

- Generally well balanced across treatment groups

except for disease duration
- Treatment groups were not balanced for extraaxial
manifestations patients
6 Aside from the experimental intervention,
were the groups treated equally?

การศึกษานี้ไมไดaระบุถึงการรักษาอื่นนอกจาก intervention
ที่ผูaปcวยไดaรับ
Section B:
What are the results?
7 How large was the treatment effect?

What outcomes were measured?

Primary outcome:
Assessment in SpondyloArthritis international Society (ASAS)
responses ประกอบไปดaวย 4 ผลลัพธยอย คือ ASAS20 response, ASAS40
response, ASAS 5/6 และ ASAS partial response

Secondary outcome:
Adverse event
7 How large was the treatment effect?

What outcomes were measured?

Is the primary outcome clearly specified?
Assessment in SpondyloArthritis international Society
(ASAS) responses
1. Disease activity was evaluated using
- BAS-DAI - Back pain VAS - Night pain VAS
- Patient’s global assessment - CRP level.
2. Physical function was evaluated using the Bath AS Functional
Index (BASFI)
 7 How large was the treatment effect?

What results were found for each outcome? Primary endpoint

Patients who received golimumab achieved an ASAS20 response

at week 14 compared with placebo group (*= P < 0.001)
 7 How large was the treatment effect?

What results were found for each outcome? Primary endpoint

Placebo Golimumab 50 mg Golimumab 100 mg P-value

Week 14
ASAS20 21.8% 59.4% 60.0% P<0.001
Week 24
ASAS20 P < 0.01
ASAS40 15.4% 43.5% 54.3%

-----------
8 How precise was the estimate of the treatment effect?

ไมมีการประเมินความแมนยําของการรักษา
 Section C:
Will the results help locally?
99. Can the results be applied to the local population,
or in your context?

การศึกษานี้สามารถใชaในกลุมผูaปcวยรพ.สงขลานครินทรไดa หากผูaปcวยตรงตามเกณฑ
ดังนี้
- ผูaปcวยผูaใหญที่เป•น Ankylosing spondylitis (AS) โดยไดaรับการวินิจฉัยจาก the
1984 New York Criteria 3 เดือน มี BASDAI score >4 และคา pain score ของ
อาการปวดไขสันหลังมากกวา 4 คะแนน
- ผูaปcวยไมตอบสนองตอการรักษาดaวย highest recommended doses NSAIDs หรือ
DMARDs เมื่อรักษาอยางนaอย 3 เดือน
9.
10 Were all clinically important outcomes considered?

Primary end point

Proportion of patients with at least 20%
improvement in AS (ASAS20) criteria at week 14
 9. Are the benefits worth the harms and costs?
11
จากการประเมินประโยชนและความเสี่ยงของการใชaยา Golimumab ซึ่ง
การศึกษาป„จจุบันไดaติดตามผูaปcวยเป•นเวลา 5 ป… พบวา ผูaปcวยมีอาการดีขึ้นจากโรคเมื่อ
เปรียบเทียบกับกลุมที่ไมไดaรับยา สําหรับ AEs ที่พบบอย คือ
- OA ที่ตaองเขaารพ. (2.0%)
- Pneumonia (1.1%)
- อาการ AS แยลง (1.1%)
- ซึมเศรaา (1.1%)
ผูaปcวยเพียง 1 ราย ที่ไดaรับ golimumab 50 mg เสียชีวิตจากมะเร็งตับออน แตไม
สามารถสรุปไดaชัดเจนถึงความสัมพันธของการใชaยาและการเกิดมะเร็งตับออน
ดังนั้น การเลือกใชaยา Golimumab ถือวามีประโยชนมากกวาโทษ
Dosage form Dose Cost
Auto-injector/Prefilled pen 50 mg/0.5 ml 55,886 bath
THANK
YOU