Colitis, Crohn's Disease, IBD, Inflammatory Bowel Disease
Conditions
Keywords
ustekinumab, moderately to severely active Crohn's Disease, tumor necrosis factor, Stelara, Crohn, Crohn's, IBD, UNITI
Brief summary
This study (UNITI-1) will compare the effects (both positive and negative) of an initial treatment with ustekinumab to placebo over 8 weeks, in patients with moderately to severely active Crohn's disease who have either failed or could not tolerate at least one TNF-antagonist medications in the past (specifically, infliximab, adalimumab, or certolizumab pegol).
Detailed description
This study (CNTO1275CRD3001 or UNITI-1) 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 who previously did not respond to, lost response to, or could not tolerate TNF-antagonist medications (specifically, infliximab, adalimumab or certolizumab pegol). 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 703 patients. 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'' \[NCT01369355\]), 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 (either placebo or ustekinumab) at the first (week 0) visit when they enter the study.There are 3 treatment groups: 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
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).
DRUGGroup 1: Placebo
Form=solution for injection, route=intravenous use, in a single dose.
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 No maximum
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's Disease Activity Index (CDAI) score of \>= 220 and \<= 450 * Have received infliximab, adalimumab, or certolizumab pegol at a dose approved for the treatment of Crohn disease and did not respond initially (ie, primary nonresponse) * Or responded initially but then lost response with continued therapy (ie, secondary nonresponse) * Or were intolerant to the medication * 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 | Baseline and Week 6 | Clinical response at Week 6 was defined as a reduction from baseline in the Crohn's Disease Activity Index 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 CDAI score of less than 150 indicates clinical remission. 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 | Baseline and Week 8 | Clinical remission is defined as a CDAI score of less than (\<) 150 points at Week 8. |
| Number of Participants in Clinical Response at Week 8 | Baseline and Week 8 | Clinical response at Week 8 was defined as a reduction from baseline in the Crohn's Disease Activity Index (CDAI) score of greater than or equal (\>=) 100 points. 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 CDAI score of less than 150 indicates clinical remission. 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 | Baseline and Week 6 | 70-point response is defined as at least 70 points reduction in CDAI score. 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 | Baseline and Week 3 | 70-point response is defined as at least 70 points reduction in CDAI score. 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, Austria, Belgium, Brazil, Canada, Czechia, Denmark, France, Germany, Hungary, Iceland, Ireland, Israel, Japan, Netherlands, New Zealand, Poland, Serbia, South Africa, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 769 participants were randomly assigned to receive study agent. The analyses (efficacy) was based on the 741 participants who were randomized after the study was restarted.
Pre-assignment details
In November 2011, due to stability issue with the batch of the intravenous (IV) drug (130 mg Ustekinumab) sponsor temporarily suspended dosing of participants with ustekinumab. Later study was restarted with 90 milligram per milliliter (mg/ml).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants randomized to receive a single dose of Placebo Intravenous (IV) infusion at week 0. | 256 |
| Ustekinumab 130 Milligram (mg) Participants randomized to receive a single dose of ustekinumab 130 milligram (mg) IV at week 0. | 254 |
| 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. | 259 |
| Total | 769 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 | 2 |
| Overall Study | Other | 2 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 6 | 10 |
Baseline characteristics
| Characteristic | Placebo | Ustekinumab 130 Milligram (mg) | Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Total |
|---|---|---|---|---|
| Age, Continuous | 37.6 years STANDARD_DEVIATION 11.86 | 37.4 years STANDARD_DEVIATION 11.74 | 37.2 years STANDARD_DEVIATION 12.57 | 37.4 years STANDARD_DEVIATION 12.05 |
| Region of Enrollment Australia | 6 participants | 7 participants | 8 participants | 21 participants |
| Region of Enrollment Austria | 0 participants | 0 participants | 6 participants | 6 participants |
| Region of Enrollment Belgium | 8 participants | 12 participants | 8 participants | 28 participants |
| Region of Enrollment Brazil | 2 participants | 0 participants | 1 participants | 3 participants |
| Region of Enrollment Canada | 10 participants | 21 participants | 21 participants | 52 participants |
| Region of Enrollment Czech Republic | 2 participants | 2 participants | 1 participants | 5 participants |
| Region of Enrollment Denmark | 1 participants | 3 participants | 2 participants | 6 participants |
| Region of Enrollment France | 17 participants | 21 participants | 29 participants | 67 participants |
| Region of Enrollment Germany | 22 participants | 14 participants | 14 participants | 50 participants |
| Region of Enrollment Hungary | 1 participants | 1 participants | 2 participants | 4 participants |
| Region of Enrollment Ireland | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Israel | 1 participants | 2 participants | 3 participants | 6 participants |
| Region of Enrollment Italy | 4 participants | 7 participants | 8 participants | 19 participants |
| Region of Enrollment Japan | 18 participants | 19 participants | 19 participants | 56 participants |
| Region of Enrollment Netherlands | 9 participants | 9 participants | 14 participants | 32 participants |
| Region of Enrollment New Zealand | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Poland | 4 participants | 3 participants | 4 participants | 11 participants |
| Region of Enrollment Serbia | 1 participants | 2 participants | 1 participants | 4 participants |
| Region of Enrollment South Africa | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment South Korea | 1 participants | 0 participants | 2 participants | 3 participants |
| Region of Enrollment Spain | 0 participants | 0 participants | 2 participants | 2 participants |
| Region of Enrollment United Kingdom | 21 participants | 21 participants | 16 participants | 58 participants |
| Region of Enrollment United States | 126 participants | 108 participants | 97 participants | 331 participants |
| Sex: Female, Male Female | 135 Participants | 153 Participants | 152 Participants | 440 Participants |
| Sex: Female, Male Male | 121 Participants | 101 Participants | 107 Participants | 329 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 | 90 / 254 | 95 / 255 | 78 / 259 |
| serious Total, serious adverse events | 18 / 254 | 14 / 255 | 18 / 259 |
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 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 CDAI score of less than 150 indicates clinical remission. A decrease in CDAI score over time indicates improvement in disease activity.
Time frame: Baseline and 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 | 53 participants |
| Ustekinumab 130 Milligram (mg) | Number of Participants With Clinical Response at Week 6 | 84 participants |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Number of Participants With Clinical Response at Week 6 | 84 participants |
p-value: 0.002Cochran-Mantel-Haenszel chi-square test
p-value: 0.003Cochran-Mantel-Haenszel chi-square test
Secondary
Number of Participants in Clinical Remission at Week 8
Clinical remission is defined as a CDAI score of less than (\<) 150 points at Week 8.
Time frame: Baseline and 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 | 18 participants |
| Ustekinumab 130 Milligram (mg) | Number of Participants in Clinical Remission at Week 8 | 39 participants |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Number of Participants in Clinical Remission at Week 8 | 52 participants |
p-value: 0.003Cochran-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 Crohn's Disease Activity Index (CDAI) score of greater than or equal (\>=) 100 points. 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 CDAI score of less than 150 indicates clinical remission. A decrease in CDAI score over time indicates improvement in disease activity.
Time frame: Baseline and 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 | 50 participants |
| Ustekinumab 130 Milligram (mg) | Number of Participants in Clinical Response at Week 8 | 82 participants |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Number of Participants in Clinical Response at Week 8 | 94 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. 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: Baseline and 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 | 67 participants |
| Ustekinumab 130 Milligram (mg) | Number of Participants With CDAI 70-point Response at Week 3 | 94 participants |
| Ustekinumab Approximately (~) 6 Milligram Per Kilogram (mg/kg) | Number of Participants With CDAI 70-point Response at Week 3 | 101 participants |
p-value: 0.009Cochran-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. 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: Baseline and 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 | 75 participants |
| Ustekinumab 130 Milligram (mg) | Number of Participants With Crohn's Disease Activity Index (CDAI) 70-point Response at Week 6 | 113 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 | 109 participants |
p-value: <0.001Cochran-Mantel-Haenszel chi-square test
p-value: 0.002Cochran-Mantel-Haenszel chi-square test