3. Results
3.1 Study selection
Four hundred sixty-one titles and abstracts were screened, 159 were
retrieved as full text articles. A total of 5 studies (published in 7
articles) met eligibility criteria and were included in the review
[3,4,32-36]. The PRISMA flowchart, depicting the process of study
selection, is shown in Figure 1.
3.2 Risk of bias and quality of evidence
Each of the domains for the five included studies were deemed low risk
of bias. The detailed assessments or risk of bias and the ratings for
quality of evidence are displayed in supplementary figures S3 and S4 and
supplementary table SI.
3.3 Study characteristics
Five double-blinded RCTs evaluating 2,899 patients with IBD initiating
treatment with VDZ were included in this review [3,4,32,33,34]. In
one study, VDZ was administered as essentially first line treatment
[32] whereas in the remaining studies, VDZ was given as atleast
second line treatment [3,4,33,34]. Follow-up time ranged from 6 to
76 weeks with a median follow-up time of 52 weeks. All of the studies
were multicenter RCTs; one study took place in Japan alone, one in the
USA and Canada, one across 5 continents, and in more than 30 countries
in the remaining two studies. Four out of the 5 included studies were
funded by pharmaceutical companies [3,4,33,34]. Table I summarizes
the characteristics of the included studies.
3.4 Study participants
The number of randomized patients in the included studies ranged from
181 to 1115 [3,4,32,33,34]. In 4 of the listed studies, mean age
ranged from 36 to 43 years [3,4,32,34]. In the fifth study, a median
age of 36 was provided [33]. In 3 of the studies, the majority of
participants were male [3,32,34], while in the remaining, the
majority were female [4,33]. Table II provides a more detailed
summary of the baseline characteristics of the participants in the
included studies.
3.5 Data from RCTs
In 2005, Feagan et al [32] published an RCT to evaluate the efficacy
of VDZ and to assess optimal dosing in patients with UC. One hundred
eighty-one patients were included, in which patients were evenly split
into three arms- placebo and two different doses of VDZ. Included
patients had evidence of active disease as measured by both clinical and
endoscopic parameters and were required to be naïve to anti-tumor
necrosis factor (TNF) therapies, and had only previously received
glucocorticoids or mesalamine. The study met its primary endpoint,
demonstrating that after 6 weeks, patients receiving VDZ (33% in the
0.5mg/kg dose group and 32% in the 2mg/kg dosage) experienced clinical
remission significantly more than those who were receiving placebo with
an overall p value of 0.03.
AEs did not differ significantly among the groups (p=0.50). Arthralgias
were experienced by 4 (7%) in the low dose group, 7 (12%) in the high
dose group, and 5 (8%) in the placebo group without a detectable
statistically significant difference among all those treated with VDZ
compared with placebo, as calculated by the authors using Fisher’s test
(p= 0.75). Further analysis yielded an OR of 1.19 with a 95% CI of
0.40-3.60 [32].
In 2013, the GEMINI 1 study group [3] conducted 2 integrated RCTs to
assess the effect of VDZ on induction and maintenance of active disease
in patients with UC. Prior TNF exposure was permitted. In the trial of
induction therapy, patients were either randomized to receive VDZ or
placebo at weeks 0 and 2, with evaluation of disease activity at the
sixth week. In the subsequent maintenance trial, participants in either
cohort who were deemed to have responded to VDZ at week 6 were
randomized to receive VDZ every 4 or 8 weeks or to receive placebo
through week 52. The study met its primary endpoint defined by a
reduction in the Mayo Clinic score of atleast 3 points and a decrease of
atleast 30% from baseline, with either a decrease of at least 1 point
on the rectal bleeding subscale or an absolute rectal bleeding score of
0 or 1. The study also met its designated primary outcome for the
maintenance phase, clinical remission at week 52.
The authors evaluated AEs by comparing all patients who had received VDZ
as maintenance therapy with the group that were given placebo during the
maintenance phase, whether they had received placebo or VDZ during
induction. They did not find significant differences in the category of
any AE (p= 0.23) as well as among serious AEs (p= 0.06) in the induction
trial. Similarly, there was no difference in any AEs in those receiving
VDZ every 8 weeks and every 4 weeks compared with placebo (p=0.65 and
0.49, respectively) nor any difference in serious AEs (p=0.06 and 0.09,
respectively) during the maintenance phase. While there was an increased
rate of development of arthralgias in those receiving VDZ during the
trial, this was not statistically significant (OR 1.01; 95% CI
0.61-1.65: p= 0.98) [3].
The GEMINI 2 study group [4] conducted a trial with an identical
design to that of the GEMINI 1 group assessing VDZ response in patients
with active CD instead. The study met part of its primary endpoint in
the trial of induction therapy evaluating for clinical remission (CDAI
≤150) at week 6 (p= 0.02) though not for clinical response (decrease in
CDAI-100 response ≥100) (p= 0.23). In the maintenance phase, the primary
endpoint of clinical remission at week 52 was achieved in patients
receiving VDZ every 8 weeks (p <0.001) and every 4 weeks (p=
0.004).
There were no significant differences in any reported AEs (p= 0.56) as
well as serious AEs (p= 0.29) in the induction trial. Similarly, there
was no difference in any AE in those receiving VDZ every 8 weeks and
every 4 weeks compared with placebo (p=0.32 and 0.86, respectively) nor
any difference in serious AEs (p=0.46 and 0.77, respectively) in the
maintenance phase. Similarly, the authors evaluated arthralgias in all
those who received VDZ in the maintenance phase compared with those who
had received placebo as maintenance, regardless of what they had
received during the induction, and did not find a statistically
significant increased rate of arthralgias (OR 1.02; 95% CI 0.69-1.50:
p= 0.92) [4].
The GEMINI 3 study group [33] conducted a phase 3 RCT to evaluate
the efficacy of VDZ in patients with moderately to severely active CD
with an objective toward assessing those who had previously failed
anti-TNF therapy. In this trial, patients were randomized to receive VDZ
or placebo (1:1) at weeks 0,2, and 6 and were assessed at week 6. This
trial did not meet its primary outcome assessing clinical remission, as
defined by CDAI≤ 150 at week 6, among those participants with prior
anti-TNF failure (p= 0.433).
There were no significant differences in the AEs (p= 0.418) and in the
drug-related AEs (p= 0.965) in patients who received VDZ compared with
placebo. Similarly, no significantly increased risk of arthralgias was
identified at week 6 in those who had received VDZ (OR 1.11; 95% CI
0.44-2.78: p= 0.831). This study also evaluated musculoskeletal pain
apart from arthralgias and found that the while there was an increased
risk of myalgias, this difference was not significant (OR 9.09; 95% CI
0.49-169.88: p= 0.140) [33].
Most recently, Motoya et al [34] performed a phrase 3 RCT in Japan
looking at patients with active UC, who were permitted to have
previously used anti-TNF agents. This study was split into a
double-blinded cohort, who were randomized to receive VDZ or placebo,
and an open label cohort who were assessed following completion of
induction, at week 10. All patients who showed a clinical response to
VDZ during induction were randomized 1:1 to receive VDZ or placebo every
8 weeks through week 54 with clinical evaluation at week 60. In
addition, anyone could receive re-induction open label VDZ followed by
treatment every 8 weeks up to 94 weeks if they had not had a clinical
response to VDZ or placebo during the induction, experienced disease
worsening, had received rescue treatment during the maintenance phase,
or completed week 60 of maintenance, with an evaluation at 16 weeks
following the last dosage received. This study did not reach its primary
endpoint for the induction phase, a clinical response at week 10, as
defined by a reduction in the full Mayo score of > 3
and atleast 30% from baseline as well as > 1 on the
rectal bleeding subscore or an absolute rectal bleeding subscore< 1 (p= 0.272). It did however meet its primary
endpoint for the maintenance phase, designated as clinical remission
(full Mayo score < 2 and no subscore > 1)
at week 60 (p= 0.021).
There was no significant difference in the development of AEs in the VDZ
group compared with placebo in the induction phase (p= 0.720) nor in the
maintenance phase (p= 0.2668). Similarly, there was no difference in the
development of serious AEs in the induction (p= 0.409) and maintenance
phases (p= 0.670). In addition, there was no significant difference in
the development of arthralgias during the induction phase (OR 1.57; 95%
CI 0.17-14.29: p= 0.688) nor during the maintenance phase (OR 10.20;
95% CI 0.53-195.78: p= 0.123) [34].
3.6: Post-hoc analyses
A post-hoc analysis of the GEMINI 2 trial [35], conducted by some of
the members of the original study group, divided patients into those
that were anti-TNF naïve and those who had previously failed anti-TNF
therapy. By stratifying the participants, the authors found that, the
risk of developing arthralgias when treated with VDZ compared with
placebo during the induction was not greater among those who had
formerly received anti-TNF agents (TNF-naïve: OR 1.26; 95% CI
0.26-6.00: p= 0.774 and TNF-failure: OR 1.24; 95% CI 0.64-2.41: p=
0.523). During the maintenance phase, on the other hand, there was an
increased risk of developing arthralgias in those who had previously
used anti-TNF treatments, though that difference was not statistically
significant (TNF-naïve: OR 0.83; 95% CI 0.37-1.84: p= 0.648 and
TNF-failure: OR 1.24; 95% CI 0.59-2.60: p= 0.566).
A second post-hoc analysis [36], also co-authored by several members
of the GEMINI study group and published 2 years later, evaluated data
from the 3 GEMINI trials. Prevalence of baseline arthritis/arthralgias,
which was the most common EIM at baseline in both patients with CD and
UC, was similar in all of the study arms assessed in GEMINI 2 and 3. As
part of further analysis, the co-authors re-divided the patients into
three groups based on whether they received: VDZ throughout, VDZ in the
induction phase followed by placebo for maintenance, and placebo alone.
They evaluated the probability of sustained resolution of
arthritis/arthralgias with prevalences of 11.9%, 15.3%, and 11.2%
according to the respective groupings. They found no significant
difference among the groups (VDZ vs placebo: hazard ratio (HR), 0.99;
95% CI, 0.52–1.90; VDZ followed by placebo vs placebo alone: HR, 1.57;
95% CI, 0.70–3.28).
Further scrutiny revealed that in the GEMINI 2 trial, the probability of
sustained resolution of arthritis/arthralgia was 51.2% in those who
received VDZ during both phases, 41.4% in those who had received VDZ
during induction followed by placebo in the maintenance phase, and
35.5% in those had had been given placebo throughout. Differences among
groups were not statistically significant (VDZ alone vs. placebo alone:
HR, 1.56; 95% CI, 0.93–2.59; VDZ followed by placebo vs placebo alone:
HR, 1.40; 95% CI, 0.75–2.64). Their analysis also revealed that
clinical response and clinical remission at weeks 6 and 52 significantly
correlated with sustained resolution of baseline arthritis/arthralgia
(p < 0.05). Evaluation of GEMINI 3 revealed sustained
resolution of baseline arthritis/arthralgia at week 10 in 22% of the
VDZ group and in 16% of the placebo group with no significant
difference detected between the 2 arms (HR, 1.40; 95% CI, 0.73–2.67)
[36].
A Cox analysis of GEMINI 2 found that when separating the participants
into those who received VDZ alone, placebo alone, and VDZ followed by
placebo, there was a significant increase in the incidence of
arthritis/arthralgias in those who received VDZ during both trial phases
and in the group who received VDZ during induction followed by placebo
compared with those who remained on placebo throughout (VDZ alone vs.
placebo alone: HR, 0.55; 95% CI 0.36–0.84); and (VDZ followed by
placebo vs. placebo alone: HR, 0.45; 95% CI, 0.26–0.81). Moreover,
patients with prior anti-TNF use were significantly more likely to
develop new joint complaints compared with those who were anti-TNF naïve
(HR, 2.20; 95% CI, 1.56–3.11) [36].
On the other hand, a Cox analysis of GEMINI 2 evaluating both new or
worsening arthritis/arthralgias revealed that such findings were less
likely in those who received VDZ and VDZ followed by placebo compared to
those who received placebo alone (VDZ alone vs. placebo alone: HR, 0.63;
95% CI, 0.44–0.89; and VDZ followed by placebo vs. placebo alone: HR,
0.54; 95% CI, 0.34–0.87). Additionally, patients with prior anti-TNF
failure were generally more likely to experience new and or worsening
arthritis/arthralgia than naïve patients (HR, 1.81; 95% CI, 1.37–2.38)
[36].