Crohn's Disease
Conditions
Brief summary
This is an open-label, interventional study where a subset of participants will be randomized to one of two treatment-optimization strategies. Participants with moderate to severe Crohn's disease (CD) will receive induction treatment comprised of 3 infusions of infliximab at Weeks 0, 2, and 6. The participants will be evaluated at Week 10. Participants who are in clinical response will enter the observational phase of the study where they will receive standard of care treatment, as per the infliximab product monograph. Participants who lose response, may qualify for entry into the interventional phase of the study, where they will be randomized to one of the following treatment-optimization arms: 1) dose increase: infliximab 7 mg/kg, every 8 weeks or 2) shortened interval: infliximab 5 mg/kg every 6 weeks. Note: Due to early study termination, no statistical analysis was performed for the interventional part of this study, therefore, endpoints dedicated to this phase of the study have not been analyzed.
Interventions
BIOLOGICALInfliximab 5 mg/kg
Participants received Infliximab 5 mg/kg intravenously (IV) at weeks 0, 2 and 6 during the induction phase. At Week 10, those who were in clinical response received further treatment every 8 weeks during the observational phase
BIOLOGICALInfliximab 5 mg/kg every 6 weeks
Participants with loss of response in the observational phase were randomized at entry into the interventional phase received 5 mg/kg IV every 6 weeks (shortened interval group)
BIOLOGICALInfliximab 7 mg/kg every 8 weeks
Participants with loss of response in the observational phase were randomized at entry into the interventional phase received 7 mg/kg IV every 8 weeks (increased dose group)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women \>=18 years of age * Moderate to severe CD (Crohn's Disease Activity Index \[CDAI\] \>= 220 and \<= 450) * CD of at least 3 months duration confirmed within the past 2 years by radiography and/or endoscopy * Biologic-naïve * If using 5-Aminosalicylic Acid (5-ASA), there must be at least 4 weeks of stable dosage prior to screening * If using azathioprine or 6-mercaptopurine, the start date must be at least 3 months prior to screening and the dose must be stable for at least 6 weeks prior to screening * If using methotrexate, the participant must have been using methotrexate with a stable dosage of at least 6 weeks prior to screening * Participants must be off corticosteroids or on a stable dose of corticosteroids for at least 2 weeks prior to enrollment. The maximal daily dose of corticosteroids at baseline must not exceed 30 mg of prednisone equivalent * Participants are considered eligible according to the following tuberculosis (TB) screening criteria: * Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination * Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB prior to or simultaneously with the first administration of study medication * Within 3 months prior to the first administration of study medication, either have negative OR have a newly identified positive diagnostic TB test result (defined as at least 1 positive tuberculin skin test) during screening in which active TB has been ruled out, and for which appropriate treatment for latent TB has been initiated either prior to or simultaneously with the first administration of study medication * Participants must have had a chest X-ray within 3 months prior to screening with no evidence of current or old active TB * Participants' screening and baseline clinical laboratory tests (complete blood count \[CBC\], blood chemistries, and urinalysis) must be within the following parameters: * Hemoglobin \>=10 g/dL (100 g/L) * White blood cells (WBCs) \>=3.5 x 109/L * Neutrophils \>=1.5 x 10\^9/L * Platelets \>=100 x 10\^9/L * Serum creatinine \<1.5 mg/dL (or \<133 μmol/L) * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and gammaglutamyltransferase \<=1.5 x upper limit of normal (ULN); * Total bilirubin \<=1 x ULN * Antibiotics for the treatment of CD (e.g., ciprofloxacin and metronidazole) must have been discontinued at least 3 weeks prior to screening * Participants must be free of any clinically significant condition or situation, other than CD that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study * Participants are willing and able to adhere to the study visit schedule and other protocol requirements * Participants are capable of providing written informed consent, which must be obtained prior to conducting any protocol-specified procedures * Sexually-active women of child-bearing potential must agree to use a medically accepted method of contraception prior to screening, while receiving protocol specified medication, and for 6 months after stopping the medication * Women of child-bearing potential who are not currently sexually active must agree to use a medically accepted method of contraception should they become sexually active while participating in the study * Female participants of childbearing potential must have a negative serum pregnancy test (beta-hCG) at screening * have an increased Harvey-Bradshaw Index (HBI) score \>=3 points over the week 10 evaluation score and a CDAI score \>=175 * have received regular infusions of Infliximab (IFX) every 8 weeks during the observational phase with a maximum interval of no more than 10 weeks between each infusions * having previous doses of IFX of \>= 4.7 mg/kg
Exclusion criteria
* Are pregnant or plan to become pregnant during the study period; participants who are breast feeding * Have been treated with excluded drugs prior to entry: any biological or anti- Tumor necrosis factor (anti-TNF) agent such as infliximab, adalimumab, certolizumab, etanercept, pentoxifylline, or thalidomide * Have had a serious infectious disease in the 8 weeks prior to entry * Have active perianal fistulas and a Perianal disease activity index (PDAI) score \>10 * Have presumed fibro-stenotic stricture or acute bowel obstruction * Have had live vaccination in the 6 weeks prior to entry * Have known intolerance to study drug * Have a history of myocardial infarction, congestive heart failure, coronary artery disease, or arrhythmias in the last 6 months * Have a history of malignancy (within the past 5 years) with the exception of carcinoma in situ of the cervix or localized basal cell skin cancer that have been adequately treated * Have a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease * Have a history of demyelinating disease such as multiple sclerosis * Have a positive test for human immunodeficiency virus (HIV), hepatitis B virus (HBV) surface antigen, or hepatitis C virus (HCV) antibody * Have renal, hepatic, hematological, cardiovascular, pulmonary, neurological, psychiatric, immunologic, gastrointestinal, endocrine, or other diseases if they are clinically significant. (A clinically significant disease is defined as one which in the opinion of the investigator can put the participants at risk because of participation in the study or a disease which can influence the participant's ability to participate in the study or affect the results of the study) * Have clinically significant abnormal laboratory test results, unless regarded by the investigator as related to CD * Have a history of alcohol or drug abuse * Are unable to comply with the protocol * Have any clinically significant findings in the physical examination that, in the investigator's judgment, may interfere with the study evaluation or affect participant safety * Are in a situation or condition that, in the opinion of the investigator, may interfere with optimal participation in the study * Are participating in any other clinical study(ies) except for registries * Are on the staff, affiliated with, or a family member of the staff personnel directly involved with this study * Are allergic to or have sensitivity to the study drug or any of its excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had a Clinical Response Using the Crohn's Disease Activity Index (CDAI) at Week 24 in the Interventional Phase | Baseline and Week 24 of the Interventional phase | The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Participants provided completed CDAI diary cards and were considered as responders in the interventional phase if their CDAI score at week 24 was decreased by 70 points or greater over their CDAI score at randomization into the interventional phase, or if their week 24 CDAI score is \<= 150. Baseline is value at randomization. |
| Mean Change From Baseline in Harvey-Bradshaw Index (HBI) | Baseline and Evaluation Week 10, Week 30 and Week 54 of the Observational Phase | Mean change in HBI score from Baseline to Week 10, 30, and 54. HBI score consists of clinical parameters: general well-being (0-4), abdominal pain (0-3), number of liquid stools per day, abdominal mass (0-3), and complications (score 1 per item). Total score is the sum of individual parameters. Minimum score is 0 and no pre-specified maximum score as it depends on the number of liquid stools. Lower scores indicate better well being. Clinical response/ long-term response is defined as a decrease by 3 or more points from baseline value. Loss of response is defined as an increase of \>= 3 points. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had a Clinical Response Using the CDAI-100 at Weeks 14-16, 24 and 48 in the Interventional Phase | Baseline and Weeks 14-16, 24 and 48 in the Interventional Phase | The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical response was defined as a 100-point reduction in CDAI score from randomization into the interventional phase or CDAI \< 150 at weeks 14-16, 24 and 48 in the Interventional Phase. Baseline is value at randomization. |
| Number of Participants That Required Treatment Optimization in the Observational Phase | Week 54 in the Observational Phase | Participants required treatment-optimization if: * Disease progression/lack of response after entering observational phase; or * Participant was successfully randomized into the interventional phase The definition of loss of response was as follows: \- An increased HBI score \>= 3 points over the week 10 evaluation score and a CDAI score \>= 175. Despite: * having received regular infusions of infliximab every 8 weeks during the observational phase with a maximum interval of no \> 10 weeks between each infusion, and * having received previous doses of infliximab of \>= 4.7 mg/kg. |
| Number of Participants Who Had Clinical Remission Off Steroids in the Interventional Phase | Weeks 14-16, 24 and 48 in the Interventional Phase | Number of participants who were in clinical remission and off systemic corticosteroids at visit. The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical remission was defined as CDAI \< 150 at weeks 14-16, 24 and 48 in the Interventional Phase. |
| Number of Participants Who Had Clinical Remission in the Interventional Phase | Weeks 14-16, 24 and 48 in the Interventional Phase | The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical remission was defined as CDAI \< 150 at weeks 14-16, 24 and 48 in the Interventional Phase. |
| Number of Participants Who Had a Clinical Response Using the CDAI at Weeks 14-16 and 48 in the Interventional Phase | Baseline and Weeks 14-16 and 48 in the Interventional Phase | The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical response was defined as a 70-point reduction in CDAI score from randomization into the interventional phase or CDAI \< 150 at week 14-16 and 48 in the Interventional Phase. Baseline is value at randomization. |
Participant flow
Pre-assignment details
Of the 100 enrolled participants, 2 participants experienced a protocol violation that excluded them from the Eligible (ELIG) population, thus, the ELIG population comprised of 98 participants. Due to early study termination, all 8 randomized participants received at least one infusion of interventional treatment, but none completed the trial.
Participants by arm
| Arm | Count |
|---|---|
| Infliximab Infliximab 5mg/kg intravenously (IV) at weeks 0, 2 and 6 during the induction phase and every 8 weeks during the observational phase and either 5mg/kg every 6 weeks or 7mg/kg every 8 weeks as determined by randomization at entry into the interventional phase. | 100 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Induction Phase | Adverse Event | 3 |
| Induction Phase | Non-responder | 14 |
| Induction Phase | Other | 3 |
| Induction Phase | Premature study termination | 14 |
| Induction Phase | Withdrawal by Subject | 1 |
| Interventional Phase | Non-responder | 2 |
| Interventional Phase | Physician Decision | 1 |
| Interventional Phase | Premature Study Termination | 5 |
| Observational Phase | Adverse Event | 1 |
| Observational Phase | Non-responder | 2 |
| Observational Phase | Other | 2 |
| Observational Phase | Premature Study Termination | 36 |
| Observational Phase | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Infliximab |
|---|---|
| Age, Continuous | 38.4 years STANDARD_DEVIATION 13.16 |
| Sex/Gender, Customized Excluded from analysis | 2 participants |
| Sex/Gender, Customized Female | 54 participants |
| Sex/Gender, Customized Male | 44 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 42 / 92 | 7 / 8 |
| serious Total, serious adverse events | 7 / 92 | 3 / 8 |
Outcome results
Primary
Mean Change From Baseline in Harvey-Bradshaw Index (HBI)
Mean change in HBI score from Baseline to Week 10, 30, and 54. HBI score consists of clinical parameters: general well-being (0-4), abdominal pain (0-3), number of liquid stools per day, abdominal mass (0-3), and complications (score 1 per item). Total score is the sum of individual parameters. Minimum score is 0 and no pre-specified maximum score as it depends on the number of liquid stools. Lower scores indicate better well being. Clinical response/ long-term response is defined as a decrease by 3 or more points from baseline value. Loss of response is defined as an increase of \>= 3 points.
Time frame: Baseline and Evaluation Week 10, Week 30 and Week 54 of the Observational Phase
Population: The eligible (ELIG) population comprised a subset of the enrolled (ENR) population who were not associated with an important protocol violation and who received at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Infliximab | Mean Change From Baseline in Harvey-Bradshaw Index (HBI) | Baseline (n= 98) | 9.5 score on a scale | Standard Deviation 3.23 |
| Infliximab | Mean Change From Baseline in Harvey-Bradshaw Index (HBI) | Change at Week 10 (n= 81) | -5.88 score on a scale | Standard Deviation 3.89 |
| Infliximab | Mean Change From Baseline in Harvey-Bradshaw Index (HBI) | Change at Week 30 (n= 37) | -7.19 score on a scale | Standard Deviation 2.998 |
| Infliximab | Mean Change From Baseline in Harvey-Bradshaw Index (HBI) | Change at Week 54 (n= 15) | -7.93 score on a scale | Standard Deviation 3.173 |
Comparison: Comparison of Infliximab from Induction baseline to evaluation Week 10.p-value: <0.0001t-test, 2 sided
Comparison: Comparison of Infliximab from Induction baseline to Week 30 of the Observational Phase.p-value: <0.0001t-test, 2 sided
Comparison: Comparison of Infliximab from Induction baseline to Week 54 of the Observational Phase.p-value: <0.0001t-test, 2 sided
Primary
Number of Participants Who Had a Clinical Response Using the Crohn's Disease Activity Index (CDAI) at Week 24 in the Interventional Phase
The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Participants provided completed CDAI diary cards and were considered as responders in the interventional phase if their CDAI score at week 24 was decreased by 70 points or greater over their CDAI score at randomization into the interventional phase, or if their week 24 CDAI score is \<= 150. Baseline is value at randomization.
Time frame: Baseline and Week 24 of the Interventional phase
Population: Due to the early termination of the study, no participants completed the Interventional phase.
Secondary
Number of Participants That Required Treatment Optimization in the Observational Phase
Participants required treatment-optimization if: * Disease progression/lack of response after entering observational phase; or * Participant was successfully randomized into the interventional phase The definition of loss of response was as follows: \- An increased HBI score \>= 3 points over the week 10 evaluation score and a CDAI score \>= 175. Despite: * having received regular infusions of infliximab every 8 weeks during the observational phase with a maximum interval of no \> 10 weeks between each infusion, and * having received previous doses of infliximab of \>= 4.7 mg/kg.
Time frame: Week 54 in the Observational Phase
Population: The eligible (ELIG) population comprised a subset of the enrolled (ENR) population who were not associated with an important protocol violation and who received at least one dose of study medication. Of the 98 participants in the ELIG population, 65 participants entered the observational phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab | Number of Participants That Required Treatment Optimization in the Observational Phase | 10 Participants |
Secondary
Number of Participants Who Had a Clinical Response Using the CDAI-100 at Weeks 14-16, 24 and 48 in the Interventional Phase
The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical response was defined as a 100-point reduction in CDAI score from randomization into the interventional phase or CDAI \< 150 at weeks 14-16, 24 and 48 in the Interventional Phase. Baseline is value at randomization.
Time frame: Baseline and Weeks 14-16, 24 and 48 in the Interventional Phase
Population: Due to the early termination of the study, no participants completed the Interventional phase.
Secondary
Number of Participants Who Had a Clinical Response Using the CDAI at Weeks 14-16 and 48 in the Interventional Phase
The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical response was defined as a 70-point reduction in CDAI score from randomization into the interventional phase or CDAI \< 150 at week 14-16 and 48 in the Interventional Phase. Baseline is value at randomization.
Time frame: Baseline and Weeks 14-16 and 48 in the Interventional Phase
Population: Due to the early termination of the study, no participants completed the Interventional phase.
Secondary
Number of Participants Who Had Clinical Remission in the Interventional Phase
The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical remission was defined as CDAI \< 150 at weeks 14-16, 24 and 48 in the Interventional Phase.
Time frame: Weeks 14-16, 24 and 48 in the Interventional Phase
Population: Due to the early termination of the study, no participants completed the Interventional phase.
Secondary
Number of Participants Who Had Clinical Remission Off Steroids in the Interventional Phase
Number of participants who were in clinical remission and off systemic corticosteroids at visit. The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \ 600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical remission was defined as CDAI \< 150 at weeks 14-16, 24 and 48 in the Interventional Phase.
Time frame: Weeks 14-16, 24 and 48 in the Interventional Phase
Population: Due to the early termination of the study, no participants completed the Interventional phase.