Tofacitinib is an oral, small-molecule Janus kinase inhibitor being investigated for ulcerative colitis (UC). In OCTAVE Induction 1 and 2, patients with moderately to severely active UC received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Clinical responders in OCTAVE Induction were re-randomized to 52 weeks' therapy with placebo, tofacitinib 5 mg BID, or tofacitinib 10 mg BID.
We conducted
A total of 121 East Asian (Japan, Korea, and Taiwan) patients were randomized in OCTAVE Induction 1 and 2 (placebo, n=26; tofacitinib 10 mg BID, n=95), and 63 in OCTAVE Sustain (placebo, n=20; tofacitinib 5 mg BID, n=22; tofacitinib 10 mg BID, n=21). At week 8 of OCTAVE Induction 1 and 2, 18.9% of patients (18/95) achieved remission with tofacitinib 10 mg BID versus 3.8% (1/26) with placebo. In OCTAVE Sustain, the week 52 remission rates were 45.5% (10/22), 47.6% (10/21), and 15.0% (3/20) with 5 mg BID, 10 mg BID, and placebo, respectively. Adverse event rates were similar between groups in OCTAVE Induction and numerically higher with tofacitinib in OCTAVE Sustain. Serious adverse event rates were similar across groups in all studies. Infections were numerically more frequent with tofacitinib than placebo. Increases in serum lipid levels were observed with tofacitinib.
In East Asian patients with UC, tofacitinib demonstrated numerically greater efficacy versus placebo as induction and maintenance therapy, with a safety profile consistent with the global study population.
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by alternating periods of relapse and remission.
Additional challenges for the effective management of UC in East Asia include delay in diagnosis and access to appropriate and affordable treatment, as well as the high prevalence of infectious diseases (e.g., hepatitis B and tuberculosis) in some Asian countries.
Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for UC. The efficacy and safety of tofacitinib for UC have been reported in a global phase 2 dose-finding study,
In the 8-week tofacitinib induction trials OCTAVE Induction 1 and 2,
We evaluated the efficacy and safety of tofacitinib in the subpopulation of patients from East Asia enrolled in the OCTAVE Induction and OCTAVE Sustain randomized controlled trials.
Efficacy and safety data from East Asian patients (patients from study centers in Japan, Korea, and Taiwan) who participated in 2 phase 3 induction studies of tofacitinib for UC (OCTAVE Induction 1 [
Patients who completed OCTAVE Induction 1 and 2 with clinical response (≥3 points and ≥30% decrease from baseline in Mayo score with accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore ≤1) were eligible to participate in the 52-week tofacitinib maintenance study, OCTAVE Sustain.
OCTAVE Induction 1 and 2 were identically designed, randomized, double-blind, placebo-controlled studies. Eligible patients were randomized (1:4) to treatment with placebo or tofacitinib 10 mg BID for 8 weeks (
The full details of the efficacy evaluations performed in OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain have been reported previously.
Health-related quality of life was assessed using the patient-reported Inflammatory Bowel Disease Questionnaire (IBDQ).
Efficacy data at week 8 of OCTAVE Induction 1 and 2 were used as baseline data in OCTAVE Sustain.
Adverse events (AEs) and clinical laboratory parameters were recorded throughout the studies. Follow-up was up to week 13 post-baseline of OCTAVE Induction 1 and 2 for patients who were not transferred into the maintenance study (OCTAVE Sustain) or the open-label extension study (OCTAVE Open), and week 57 post-baseline of OCTAVE Sustain for patients who were not transferred into OCTAVE Open.
In these
Descriptive statistics are presented for patients receiving placebo, tofacitinib 5 mg BID (OCTAVE Sustain only), and tofacitinib 10 mg BID. Treatment differences and 95% CIs were calculated using the normal approximation for the difference in binomial proportions. Data from the 3 East Asian patients (all of whom were from Japan) randomized to tofacitinib 15 mg BID in OCTAVE Induction 1 and 2 were not included in the induction study efficacy and safety evaluation. The primary efficacy analyses in OCTAVE Sustain included patients who received tofacitinib 15 mg BID in the induction study. A sensitivity analysis was performed for analysis of binary clinical efficacy end points in OCTAVE Sustain, in which patients who received tofacitinib 15 mg BID in the induction study were excluded. These 3 patients were included in the OCTAVE Sustain safety evaluations.
These studies were conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines, and were approved by the institutional review boards and/or independent ethics committees at each of the investigational centers participating in the studies or a central institutional review board. All patients provided written informed consent.
Globally, 1,207 patients were randomized in OCTAVE Induction 1 and 2 (including patients randomized to tofacitinib 15 mg BID). This subpopulation analysis included 121 patients from East Asia who were randomized and treated in OCTAVE Induction 1 and 2 (62 patients from Japan, 57 from Korea, and 2 from Taiwan). Twenty-six patients received placebo and 95 received tofacitinib 10 mg BID. One patient (3.8%) receiving placebo and 6 patients (6.3%) receiving tofacitinib 10 mg BID dropped out of the study (
A total of 593 patients were re-randomized globally in OCTAVE Sustain, of whom 63 were from East Asia (39 from Japan, 23 from Korea, and 1 from Taiwan). Twenty patients received placebo, 22 received tofacitinib 5 mg BID, and 21 received tofacitinib 10 mg BID. Eleven patients (55.0%) receiving placebo, 6 (27.3%) receiving tofacitinib 5 mg BID, and 7 (33.3%) receiving tofacitinib 10 mg BID discontinued (
A numerically greater proportion of East Asian patients receiving tofacitinib 10 mg BID (18/95, 18.9%) achieved the primary end point of remission at week 8 versus placebo-treated patients (1/26, 3.8%; difference from placebo [95% CI]: 15.1% [4.3, 25.9]) (
A numerically greater proportion of East Asian patients receiving tofacitinib 5 mg BID (10/22, 45.5%) and tofacitinib 10 mg BID (10/21, 47.6%) achieved the primary end point of remission at week 52 versus placebo-treated patients (3/20, 15.0%) (
In the primary analysis, the rates of clinical response (
Improvements in partial Mayo score gained during OCTAVE Induction 1 and 2 were maintained across all treatment groups in OCTAVE Sustain (
The baseline (SD) mean IBDQ total score was 129.0 (29.4) in the placebo group and 135.8 (28.9) in the tofacitinib 10 mg BID group. Treatment with tofacitinib 10 mg BID resulted in numerically greater improvements from baseline versus placebo in the IBDQ total score and in all IBDQ domain scores at weeks 4 and 8. The mean change from baseline in total IBDQ score with tofacitinib 10 mg BID was 22.5 at week 4 and 27.4 at week 8. The respective values with placebo were 11.5 and 14.9. For the Bowel Function Score, the week 8 mean change from baseline was 10.6 with tofacitinib 10 mg BID versus 6.6 with placebo (week 4: 8.5 vs. 4.7, respectively). For the Emotional Status Score, the mean changes from baseline were 7.5 versus 5.0 at week 8 and 6.6 versus 4.6 at week 4 for tofacitinib 10 mg BID and placebo, respectively. The respective changes from baseline in the Systemic Symptoms Score were 4.3 versus 2.1 at week 8 and 3.3 versus 0.9 at week 4. For the Social Function Score, the changes from baseline were 5.1 versus 1.2 at week 8 and 4.1 versus 1.3 at week 4 in the tofacitinib and placebo groups, respectively. IBDQ remission at week 8 was achieved by 56.8% of tofacitinib-treated patients versus 15.4% of patients with placebo (44.2% vs. 19.2% at week 4), and IBDQ response at week 8 was achieved by 62.1% of tofacitinib-treated patients versus 38.5% of those with placebo (55.8% vs. 34.6% at week 4).
The mean (SD) IBDQ score at baseline of OCTAVE Sustain was 164.0 (26.8) in the placebo group, 174.0 (10.9) in the tofacitinib 5 mg BID group, and 166.4 (18.8) in the tofacitinib 10 mg BID group. The mean changes from baseline in the total IBDQ score at week 52 of OCTAVE Sustain were 3.1 with tofacitinib 5 mg BID and 9.9 with tofacitinib 10 mg BID, compared with −1.0 with placebo. The mean changes from baseline in the Bowel Function Score at week 52 were −0.8 with tofacitinib 5 mg BID, 3.4 with tofacitinib 10 mg BID, and 0.8 with placebo. For the Emotional Status Score, the week 52 mean changes from baseline were 3.4 and 3.0 with tofacitinib 5 mg BID and 10 mg BID, respectively, versus −1.3 with placebo. For the Systemic Symptoms Score, the mean changes from baseline at week 52 were 0.3 with tofacitinib 5 mg BID, 1.5 with tofacitinib 10 mg BID, and −0.8 with placebo. For the Social Function Score, the week 52 changes from baseline were 0.1 and 2.1 with tofacitinib 5 mg BID and 10 mg BID, respectively, and 0.3 with placebo. At week 52 of OCTAVE Sustain, 50.0% of patients in the tofacitinib 5 mg BID group, 42.9% of patients in the tofacitinib 10 mg BID group, and 15.0% of patients in the placebo group achieved IBDQ remission. IBDQ response at week 52 was achieved by 40.9% and 52.4% of patients receiving tofacitinib 5 mg BID and tofacitinib 10 mg BID, respectively, versus 30.0% of patients receiving placebo.
The proportion of East Asian patients in OCTAVE Induction 1 and 2 who experienced AEs was similar for the group receiving tofacitinib 10 mg BID versus those receiving placebo (
In OCTAVE Sustain, the proportion of patients who experienced AEs was numerically higher with both doses of tofacitinib versus placebo. There were 3 SAEs in OCTAVE Sustain: 2 with placebo (diverticulitis in 1 patient and venous embolism in 1 patient) and 1 with tofacitinib 5 mg BID (lumbar vertebral fracture). One patient in the placebo group discontinued because of an AE, and there were no discontinuations owing to AEs with tofacitinib 5 mg BID or tofacitinib 10 mg BID.
In OCTAVE Induction 1 and 2, infections occurred more frequently with tofacitinib treatment (22.1%) than with placebo (11.5%). One serious infection (
There was one adjudicated opportunistic infection in East Asian patients during OCTAVE Induction 1 and 2. The patient was receiving tofacitinib 10 mg BID and experienced an AE of herpes zoster (non-serious and moderate in severity) on day 22 of the study, which was adjudicated as an opportunistic infection based on multidermatomal involvement. The patient did not discontinue tofacitinib, and completed the study. There were no East Asian patients with opportunistic infections in OCTAVE Sustain, and none had herpes zoster AEs.
There were no intestinal perforation AEs, adjudicated cardiovascular events, adjudicated malignancy events, tuberculosis events, or deaths with tofacitinib treatment in the East Asian population of patients in OCTAVE Induction 1 and 2 and OCTAVE Sustain.
Changes from baseline in clinical laboratory parameters in the East Asian patient population during OCTAVE Induction 1 and 2 and OCTAVE Sustain are summarized in
In these
During the 8-week induction studies and 52-week maintenance study, the safety profile of tofacitinib 5 mg BID and tofacitinib 10 mg BID in East Asian patients was largely consistent with the results of the global analysis.
The treatment effect sizes observed with tofacitinib in the East Asian OCTAVE Induction 1 and 2 population for clinical remission, mucosal healing, and clinical response end points were broadly in line with the range reported for induction therapy in global studies of infliximab,
Importantly, the OCTAVE studies included a more stringent definition of remission, in which patients were required to have a rectal bleeding subscore of 0 in addition to the requirements for clinical remission (total Mayo score ≤2 and no individual subscore >1) in the studies of infliximab, adalimumab, and vedolizumab.
The efficacy of tofacitinib demonstrated in these analyses of East Asian patients is in contrast to that observed with adalimumab in a study of 273 Japanese patients with moderately to severely active UC.
A limitation of these analyses was that the East Asian patient population was relatively small, and the comparison of efficacy and safety between the treatment groups was based on descriptive statistics only. In addition to the relatively small sample size in these East Asian analyses, the 1:4 randomization ratio resulted in a small number of patients in the placebo groups of OCTAVE Induction 1 and 2. Thus, the ability to detect and compare AEs with low occurrence rates was limited. An ongoing open-label extension study (OCTAVE Open,
In conclusion, in the East Asian population of patients in OCTAVE Induction 1 and 2, tofacitinib 10 mg BID was efficacious and well tolerated as an induction therapy for moderate to severe UC. In East Asian patients in OCTAVE Sustain, tofacitinib 5 mg and tofacitinib 10 mg BID demonstrated greater observed treatment effects versus placebo as maintenance therapy. No new safety signals were observed. The efficacy and safety of tofacitinib in East Asian patients were generally consistent with observations in the global study populations, and we detected no difference in the response of East Asian patients to tofacitinib therapy compared with the overall study populations.
The authors would like to thank the patients, investigators, and study teams who were involved in OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain, as well as Paul Healey (who was an employee and stockholder of Pfizer Inc at the time of the analyses) for his contribution to the manuscript.
Characteristics | OCTAVE Induction 1 and 2 | OCTAVE Sustain | |||
---|---|---|---|---|---|
Placebo (n=26) | Tofacitinib 10 mg BID (n=95) | Placebo (n=20) | Tofacitinib 5 mg BID (n=22) | Tofacitinib 10 mg BID (n=21) | |
Male sex | 15 (57.7) | 58 (61.1) | 10 (50.0) | 13 (59.1) | 12 (57.1) |
Age (yr) | 39.4±14.1 | 42.1±13.5 | 44.4±15.1 | 41.5±15.0 | 43.0±11.6 |
Induction study treatment | |||||
Placebo | - | - | 1 (5.0) | 3 (13.6) | 1 (4.8) |
Tofacitinib 10 mg BID | - | - | 18 (90.0) | 18 (81.8) | 19 (90.5) |
Tofacitinib 15 mg BID | - | - | 1 (5.0) | 1 (4.5) | 1 (4.8) |
In remission at maintenance study baseline | - | - | 3 (15.0) | 9 (40.9) | 8 (38.1) |
Weight (kg) | 59.5±11.7 | 61.8±12.7 | 62.1±8.5 | 59.7±11.0 | 63.3±13.8 |
Duration of disease (yr) | 5.3 (1.6–15.2) | 7.6 (0.8–25.5) | 8.4 (1.0–25.2) | 9.8 (2.2–25.1) | 10.5 (2.1–24.0) |
Extent of disease | |||||
Proctosigmoiditis | 1 (3.8) | 9 (9.5) | 1 (5.0)a | 1 (4.5)a | 3 (14.3)a |
Left-sided colitis | 8 (30.8) | 23 (24.2) | 5 (25.0)a | 7 (31.8)a | 6 (28.6)a |
Extensive/pancolitis | 17 (65.4) | 63 (66.3) | 14 (70.0)a | 14 (63.6)a | 12 (57.1)a |
Total Mayo score | 9.0±1.5 | 8.6±1.5 | 3.8±1.9 | 2.9±1.5 | 3.0±2.0 |
Partial Mayo score | 6.3±1.3 | 5.9±1.3 | 1.8±1.4 | 1.3±0.8 | 1.5±1.2 |
IBDQ total score | 129.0±29.4 | 135.8±28.9 | 164.0±26.8 | 174.0±10.9 | 166.4±18.8 |
Baseline CRP category (mg/L) | |||||
≤3 | 9 (34.6) | 49 (51.6) | 17 (85.0) | 19 (86.4) | 19 (90.5) |
>3 | 17 (65.4) | 46 (48.4) | 3 (15.0) | 3 (13.6) | 2 (9.5) |
≤6 | 14 (53.8) | 64 (67.4) | 17 (85.0) | 22 (100.0) | 19 (90.5) |
>6 | 12 (46.2) | 31 (32.6) | 3 (15.0) | 0 | 2 (9.5) |
Prior anti-TNF treatment | 15 (57.7) | 52 (54.7) | 9 (45.0)a | 7 (31.8)a | 12 (57.1)a |
Prior anti-TNF failure | 14 (53.8) | 49 (51.6) | 9 (45.0)a | 7 (31.8)a | 11 (52.4)a |
Prior immunosuppressant failure | 24 (92.3) | 78 (82.1) | 16 (80.0)a | 18 (81.8)a | 17 (81.0)a |
Prior corticosteroid treatment | 25 (96.2) | 86 (90.5) | NA | NA | NA |
Steroid use at baseline (mg/day) | 9 (34.6) | 27 (28.4) | 8 (40.0)a | 6 (27.3)a | 7 (33.3)a |
<15 | 7 (77.8) | 20 (74.1) | NA | NA | NA |
≥15 | 2 (22.2) | 7 (25.9) | NA | NA | NA |
Smoking status | |||||
Never smoked | 17 (65.4) | 56 (58.9) | 8 (40.0)a | 16 (72.7)a | 14 (66.7)a |
Current smoker | 3 (11.5) | 3 (3.2) | 1 (5.0)a | 0a | 1 (4.8)a |
Ex-smoker | 6 (23.1) | 36 (37.9) | 11 (55.0)a | 6 (27.3)a | 6 (28.6)a |
Values are presented as number (%), mean±SD, or median (range). The baseline values for OCTAVE Sustain are at the time of randomization into OCTAVE Sustain, except where indicated.
aIndicated values are at baseline of OCTAVE Induction 1 and 2.
BID, twice daily; IBDQ, Inflammatory Bowel Disease Questionnaire; NA, not available; anti-TNF, anti-tumor necrosis factor.
Event | OCTAVE Induction 1 and 2 | OCTAVE Sustain | |||
---|---|---|---|---|---|
Placebo (n=26) | Tofacitinib 10 mg BID (n=95) | Placebo (n=20) | Tofacitinib 5 mg BID (n=22) | Tofacitinib 10 mg BID (n=21) | |
AEs | 14 (53.8) | 46 (48.4) | 15 (75.0) | 20 (90.9) | 17 (81.0) |
SAEs | 1 (3.8) | 2 (2.1) | 2 (10.0) | 1 (4.5) | 0 |
Discontinuations because of AEs | 0 | 1 (1.1) | 1 (5.0) | 0 | 0 |
Discontinuation because of insufficient clinical response | 1 (3.8) | 3 (3.2) | 10 (50.0) | 6 (27.3) | 6 (28.6) |
Infections | 3 (11.5) | 21 (22.1) | 6 (30.0) | 13 (59.1) | 10 (47.6) |
Herpes zoster | 0 | 1 (1.1) | 0 | 0 | 0 |
Serious infections | 0 | 1 (1.1) | 1 (5.0) | 0 | 0 |
Opportunistic infections | 0 | 1 (1.1) | 0 | 0 | 0 |
Most frequent AEsa | |||||
Nasopharyngitis | 3 (11.5) | 6 (6.3) | 2 (10.0) | 5 (22.7) | 5 (23.8) |
Upper RTI | 0 | 5 (5.3) | 2 (10.0) | 5 (22.7) | 2 (9.5) |
Worsening UC | 0 | 1 (1.1) | 5 (25.0) | 5 (22.7) | 0 |
Arthralgia | 2 (7.7) | 0 | 4 (20.0) | 2 (9.1) | 0 |
Abdominal pain upper | 1 (3.8) | 3 (3.2) | 2 (10.0) | 0 | 0 |
Anemia | 2 (7.7) | 3 (3.2) | 0 | 0 | 0 |
Values are presented as number (%). Patients with insufficient clinical response included those who discontinued because of an adverse event (AE) of worsening UC.
aThe 4 most frequently occurring AEs overall in OCTAVE Induction 1 and 2, and OCTAVE Sustain, are presented for each treatment group in OCTAVE Induction 1 and 2 and OCTAVE Sustain.
BID, twice daily; SAE, serious adverse event; RTI, respiratory tract infection.
Laboratory parameter | OCTAVE Induction 1 and 2 | OCTAVE Sustain | |||
---|---|---|---|---|---|
Placebo (n=25) | Tofacitinib 10 mg BID (n=92) | Placebo (n=10) | Tofacitinib 5 mg BID (n=16) | Tofacitinib 10 mg BID (n=14) | |
Total cholesterol | 3.9±9.9 | 21.8±18.3 | −7.2±11.7 | 4.1±13.7 | 6.2±13.3 |
LDL | 3.1±13.9 | 21.6±27.9 | 3.9±24.2 | 10.6±21.9 | 14.1±25.8 |
HDL | 4.8±14.3 | 29.5±23.0a | −16.1±11.0 | −1.3±19.1 | 3.3±19.4 |
Triglycerides | 12.1±32.9 | 9.2±55.6 | 9.0±42.3 | 13.4±47.0 | 3.3±42.4 |
Total cholesterol/HDL ratio | −0.0±8.9 | −4.9±13.0a | 11.4±14.4 | 7.5±15.3 | 4.9±16.4 |
LDL/HDL ratio | −0.6±14.0 | −5.4±19.0a | 25.6±34.0 | 15.0±27.1 | 12.8±26.0 |
CK | 7.7 | 73.0 | −7.9 | −4.0 | 17.0 |
Values are presented as mean±SD or median. Percent change from baseline in lipid profile and CK at week 8 in OCTAVE Induction 1 and 2, and at week 52 in OCTAVE Sustain.
an=91.
BID, twice daily.