Colitis, Crohn's Disease, IBD, Inflammatory Bowel Disease
Conditions
Keywords
ustekinumab, moderately to severely active Crohn's Disease, Stelara, IBD, colitis, crohn, UNITI, Crohn's
Brief summary
This study (UNITI-2) will compare the effects (both positive and negative) of an initial treatment with ustekinumab to a placebo over 8 weeks in patients with moderately to severely active Crohn's disease.
Detailed description
This study (CNTO1275CRD3002 or UNITI-2) examines ustekinumab (an antibody medication that inhibits the inflammatory proteins IL-12 and IL-23) versus a placebo (otherwise identical except without the ustekinumab antibody) given intravenously (by an IV) in adults with moderately to severely active Crohn's disease. Ustekinumab (also known as Stelara) is approved as a treatment for the skin condition of moderate to severe plaque-type psoriasis, but this study will examine if ustekinumab can provide benefit in Crohn's disease and also assess for any risks or side effects. Both the positive and negative outcomes of IV placebo versus two different doses of IV ustekinumab will be tracked and compared over eight weeks, in approximately 612 patients who have previously failed or were intolerant to corticosteroids or immunomodulators (methotrexate, azathioprine, or 6-mercaptopurine) or are dependent on corticosteroid medications. Patients enrolling in this study will be assigned to one of the 3 treatment groups by chance (randomly, like rolling dice), and all will receive a single IV administration of study agent at the first study visit (after the screening period), and then will be asked to return for 3 additional visits through Week 8. Patients who complete this study through the Week 8 visit and remain eligible can enter the maintenance study (CNTO1275CRD3003 or IM-UNITI), where they will receive additional study agent, including the administration of ustekinumab in patients who receive placebo in this study and have not had improvement in their Crohn's disease. Patients who do not enter the CNTO1275CRD3003 study will have a final safety follow-up visit approximately 20 weeks after they received study agent when they entered into this study at the Week 0 visit. .All patients will receive a single intravenous (IV) administration of study drug (placebo or ustekinumab) at the start of the study.There are 3 treatment groups in this study: Group 1: Placebo; Group 2: ustekinumab 130 mg, Group 3: weight-range based ustekinumab doses approximating ustekinumab 6 mg/kg: 260 mg (weight \<= 55 kg), 390 mg (weight \> 55 kg and \<= 85 kg), and 520 mg (weight \> 85 kg).
Interventions
DRUGGroup 1: Placebo
Form=solution for injection, route=intravenous use, in a single dose.
Type=exact, unit=mg, number=130, form=solution for injection, route= intravenous use, in a single dose.
Type=range, unit=mg/kg, number=6, form=solution for injection, route= intravenous use, in a single dose.weight-range based ustekinumab doses approximating ustekinumab 6 mg/kg: 260 mg (weight \<= 55 kg), 390 mg (weight \> 55 kg and \<= 85 kg), and 520 mg (weight \> 85 kg).
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Have Crohn's disease of at least 3 months' duration with colitis, ileitis, or ileocolitis, confirmed at some time in the past by radiography, histology, or endoscopy * Have active Crohn's disease, defined as a baseline Crohn Disease Activity Index (CDAI) score of \>= 220 and \<= 450, with confirmation of active inflammation * Has failed conventional therapy as demonstrated by having received corticosteroids and/or immunomodulators(ie, AZA, MTX, or 6-MP) at adequate therapeutic doses OR Have a history of failure to respond to or tolerate an adequate course of corticosteroids and/or immunomodulators (ie, AZA, MTX, or 6-MP) at adequate therapeutic doses OR Is corticosteroid dependent or has had a history of corticosteroid dependency AND Has not previously demonstrated failure of or intolerance to 1 or more TNF-antagonist therapies (ie, infliximab, adalimumab, or certolizumab pegol) per study criteria * Have screening laboratory test results within protocol-specified parameters
Exclusion criteria
* Patients who have had any kind of bowel resection within 6 months * Are pregnant or planning pregnancy (both men and women) while enrolled in the study or for 20 weeks after receiving study agent * Patients who have received infliximab, adalimumab or certolizumab pegol \< = 8 weeks before the first administration of study drug * Patients with certain complications of Crohn's disease that would make it hard to assess response to study drug * Patients with a history of or ongoing chronic or recurrent infectious disease * Patients who have previously received a biologic agent targeting IL-12 or IL-23, including but not limited to ustekinumab (CNTO 1275) or briakinumab (ABT-874)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Response at Week 6 | Week 6 | Clinical response at Week 6 was defined as a reduction from baseline in the Crohn's Disease Activity Index (CDAI) score of greater than or equal (\>=) 100 points (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). Participants with a baseline CDAI score of \> = 220 to less than or equal (\< =) 248 were considered to be in clinical response if a CDAI score of less than (\<) 150 was attained. A decrease in CDAI score over time indicates improvement in disease activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants in Clinical Remission at Week 8 | Week 8 | Clinical remission at Week 8 was defined as a Crohn's Disease Activity Index (CDAI) score of \<150 points. |
| Number of Participants in Clinical Response at Week 8 | Week 8 | Clinical response at Week 8 was defined as a reduction from baseline in the CDAI score of greater than or equal (\>=) 100 points (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). Participants with a baseline CDAI score of \> = 220 to less than or equal (\< =) 248 were considered to be in clinical response if a CDAI score of less than (\<) 150 was attained. A decrease in CDAI score over time indicates improvement in disease activity. |
| Number of Participants With Crohn's Disease Activity Index (CDAI) 70 Point Response at Week 6 | Week 6 | 70-point response is defined as at least 70 points reduction in CDAI score (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A decrease in CDAI over time indicates improvement in disease activity. |
| Number of Participants With CDAI 70 Point Response at Week 3 | Week 3 | 70-point response is defined as at least 70 points reduction in CDAI score (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A decrease in CDAI over time indicates improvement in disease activity. |
Countries
Australia, Belgium, Brazil, Bulgaria, Canada, Croatia, France, Germany, Hungary, Iceland, Israel, Japan, Netherlands, New Zealand, Poland, Russia, Serbia, South Africa, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 640 participants were randomly assigned to receive study agent. The analyses (efficacy) were based on the 628 participants who were randomized after the study was restarted. However, one additional participant was excluded from efficacy analyses due to misconduct by the investigative site.
Pre-assignment details
In November 2011, due to stability issue with the batch of the IV drug (130 mg Ustekinumab) sponsor temporarily suspended dosing of participants with ustekinumab. Study was restarted with 90 mg/ml on 17 February 2012.
Participants by arm
| Arm | Count |
|---|---|
| Placebo IV Participants randomized to receive a single dose of Placebo Intravenous (IV) infusion at week 0. | 214 |
| Ustekinumab 130 Milligram (mg) Participants randomized to receive a single dose of ustekinumab 130 milligram (mg) IV at week 0. | 213 |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) Participants randomized to receive tiered ustekinumab dose approximately (\
) 6 mg/kg IV at week 0. Ustekinumab 260 mg for participants body weight less than or equal to (\< =) 55 kg, ustekinumab 390 mg for weight greater than (\>) 55 kg and \< = 85 kg and ustekinumab 520 mg for weight \> 85 kg. | 213 |
| Total | 640 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 2 | 1 |
| Overall Study | Not Treated | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 7 | 2 |
Baseline characteristics
| Characteristic | Placebo IV | Ustekinumab 130 Milligram (mg) | Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Total |
|---|---|---|---|---|
| Age, Continuous | 40.1 years STANDARD_DEVIATION 13.09 | 39.2 years STANDARD_DEVIATION 13.74 | 38.8 years STANDARD_DEVIATION 13.65 | 39.4 years STANDARD_DEVIATION 13.48 |
| Gender Female | 113 Participants | 107 Participants | 122 Participants | 342 Participants |
| Gender Male | 101 Participants | 106 Participants | 91 Participants | 298 Participants |
| Region of Enrollment Australia | 8 participants | 7 participants | 5 participants | 20 participants |
| Region of Enrollment Belgium | 1 participants | 1 participants | 2 participants | 4 participants |
| Region of Enrollment Brazil | 2 participants | 5 participants | 2 participants | 9 participants |
| Region of Enrollment Bulgaria | 8 participants | 5 participants | 11 participants | 24 participants |
| Region of Enrollment Canada | 14 participants | 18 participants | 10 participants | 42 participants |
| Region of Enrollment Croatia | 1 participants | 2 participants | 1 participants | 4 participants |
| Region of Enrollment France | 3 participants | 2 participants | 5 participants | 10 participants |
| Region of Enrollment Germany | 19 participants | 15 participants | 13 participants | 47 participants |
| Region of Enrollment Hungary | 23 participants | 20 participants | 18 participants | 61 participants |
| Region of Enrollment Iceland | 0 participants | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Israel | 2 participants | 3 participants | 6 participants | 11 participants |
| Region of Enrollment Italy | 2 participants | 2 participants | 5 participants | 9 participants |
| Region of Enrollment Japan | 9 participants | 8 participants | 9 participants | 26 participants |
| Region of Enrollment Korea | 7 participants | 7 participants | 6 participants | 20 participants |
| Region of Enrollment Netherland | 1 participants | 1 participants | 2 participants | 4 participants |
| Region of Enrollment New Zealand | 2 participants | 8 participants | 4 participants | 14 participants |
| Region of Enrollment Poland | 8 participants | 8 participants | 10 participants | 26 participants |
| Region of Enrollment Russia | 6 participants | 6 participants | 5 participants | 17 participants |
| Region of Enrollment Serbia | 4 participants | 8 participants | 3 participants | 15 participants |
| Region of Enrollment South Africa | 14 participants | 5 participants | 14 participants | 33 participants |
| Region of Enrollment Spain | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United Kingdom | 8 participants | 8 participants | 5 participants | 21 participants |
| Region of Enrollment United States | 72 participants | 72 participants | 76 participants | 220 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 44 / 212 | 40 / 216 | 44 / 211 |
| serious Total, serious adverse events | 15 / 212 | 10 / 216 | 9 / 211 |
Outcome results
Primary
Number of Participants With Clinical Response at Week 6
Clinical response at Week 6 was defined as a reduction from baseline in the Crohn's Disease Activity Index (CDAI) score of greater than or equal (\>=) 100 points (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). Participants with a baseline CDAI score of \> = 220 to less than or equal (\< =) 248 were considered to be in clinical response if a CDAI score of less than (\<) 150 was attained. A decrease in CDAI score over time indicates improvement in disease activity.
Time frame: Week 6
Population: Efficacy analyses set included all the participants who were randomized after the study was restarted.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Clinical Response at Week 6 | 60 participants |
| Ustekinumab 130 mg | Number of Participants With Clinical Response at Week 6 | 108 participants |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Number of Participants With Clinical Response at Week 6 | 116 participants |
p-value: <0.001Cochran-Mantel-Haenszel chi-square test
p-value: <0.001Cochran-Mantel-Haenszel chi-square test
Secondary
Number of Participants in Clinical Remission at Week 8
Clinical remission at Week 8 was defined as a Crohn's Disease Activity Index (CDAI) score of \<150 points.
Time frame: Week 8
Population: Efficacy analyses set included all the participants who were randomized after the study was restarted.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants in Clinical Remission at Week 8 | 41 participants |
| Ustekinumab 130 mg | Number of Participants in Clinical Remission at Week 8 | 64 participants |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Number of Participants in Clinical Remission at Week 8 | 84 participants |
p-value: 0.009Cochran-Mantel-Haenszel chi-square test
p-value: <0.001Cochran-Mantel-Haenszel chi-square test
Secondary
Number of Participants in Clinical Response at Week 8
Clinical response at Week 8 was defined as a reduction from baseline in the CDAI score of greater than or equal (\>=) 100 points (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). Participants with a baseline CDAI score of \> = 220 to less than or equal (\< =) 248 were considered to be in clinical response if a CDAI score of less than (\<) 150 was attained. A decrease in CDAI score over time indicates improvement in disease activity.
Time frame: Week 8
Population: Efficacy analyses set included all the participants who were randomized after the study was restarted.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants in Clinical Response at Week 8 | 67 participants |
| Ustekinumab 130 mg | Number of Participants in Clinical Response at Week 8 | 99 participants |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Number of Participants in Clinical Response at Week 8 | 121 participants |
p-value: <0.001Cochran-Mantel-Haenszel chi-square test
p-value: <0.001Cochran-Mantel-Haenszel chi-square test
Secondary
Number of Participants With CDAI 70 Point Response at Week 3
70-point response is defined as at least 70 points reduction in CDAI score (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A decrease in CDAI over time indicates improvement in disease activity.
Time frame: Week 3
Population: Efficacy analyses set included all the participants who were randomized after the study was restarted.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With CDAI 70 Point Response at Week 3 | 66 participants |
| Ustekinumab 130 mg | Number of Participants With CDAI 70 Point Response at Week 3 | 103 participants |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Number of Participants With CDAI 70 Point Response at Week 3 | 106 participants |
p-value: <0.001Cochran-Mantel-Haenszel chi-square test
p-value: <0.001Cochran-Mantel-Haenszel chi-square test
Secondary
Number of Participants With Crohn's Disease Activity Index (CDAI) 70 Point Response at Week 6
70-point response is defined as at least 70 points reduction in CDAI score (in general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities). The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A decrease in CDAI over time indicates improvement in disease activity.
Time frame: Week 6
Population: Efficacy analyses set included all the participants who were randomized after the study was restarted.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Crohn's Disease Activity Index (CDAI) 70 Point Response at Week 6 | 81 participants |
| Ustekinumab 130 mg | Number of Participants With Crohn's Disease Activity Index (CDAI) 70 Point Response at Week 6 | 123 participants |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Number of Participants With Crohn's Disease Activity Index (CDAI) 70 Point Response at Week 6 | 135 participants |
p-value: <0.001Cochran-Mantel-Haenszel chi-square test
p-value: <0.001Cochran-Mantel-Haenszel chi-square test