Induction Optimization With Stelara for Crohn's Disease

Study Overview
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Brief Summary
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This is a 16-week randomized controlled trial comparing a second IV weight-based induction dose at week 8 to standard 90mg subcutaneous dose at week 8, with a primary endpoint of clinical remission at week 16.

Official Title
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Induction Optimization With Stelara for Crohn's Disease

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: Ustekinumab
* Drug: Ustekinumab
* Drug: Ustekinumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females between the ages of 18 and 70 History of Crohn's disease for at least 3 months confirmed by colonoscopy and/or cross sectional imaging reviewed by the PI Moderate to Severe Crohn's disease defined as a CDAI between 220 and 450 Either a CRP >8mg/L or a fecal calprotectin > 250ug/g within 4 weeks of starting ustekinumab Stable Concomitant medications (prior to first dose of ustekinumab) Stable dose of 6-MP, azathioprine, or methotrexate for at least 4 weeks Stable dose of oral mesalamine for at least 2 weeks Stable dose of prednisone of 20mg or less or budesonide 9mg daily for at least 2 weeks If subject is a female, before randomization she must be: a. Postmenopausal, defined as ≥ 45 years of age with amenorrhea for at least 18 months, OR ≥ 45 years of age with amenorrhea for at least 6 months and a serum FSH level > 40 IU/mL OR b. Of childbearing potential, in which case she must satisfy at least one of the below: Surgically sterile (has had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or If heterosexually active, practicing a highly effective method of birth control, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (eg, condoms, diaphragm, or cervical cap, with spermicidal foam, cream, film, gel or suppository), or male partner sterilization, consistent with local regulations regarding use of birth control methods for subjects participating in clinical trials, for a period of 16 weeks after the last administration of study agent, OR Not heterosexually active. Note: If a woman participant's childbearing potential changes after start of the study (e.g., a pre-menarchal woman experiences menarche) or if women of childbearing potential who are not heterosexually active at screening become heterosexually active, they must agree to utilize a highly effective method of birth control, as described above. Female participants of childbearing potential (menstrual and not surgically sterile), must have a negative serum beta-human chorionic gonadotropin (ᵦ-hCG) pregnancy test at screening and a negative urine pregnancy test at Week 0 (prior to randomization) and agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 16 weeks after the last administration of study agent. Male participants who are not surgically sterilized and are heterosexually active with a woman of childbearing potential, must agree to use a barrier method of contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository) and to not donate sperm during the study and for 16 weeks after last receiving study agent. Note that barrier methods must also be used in all male subjects sexually active with pregnant partners for at least 16 weeks after last study agent administration. Exclusion Criteria: Past Stelara or anti-IL 23 use. Active infection. Has any known malignancy or has a history of malignancy (except for basal cell carcinoma; squamous cell carcinoma in situ of the skin; or cervical carcinoma in situ that has been treated with no evidence of recurrence; or squamous cell carcinoma of the skin that has been treated with no evidence of recurrence within 5 years prior to screening). Indeterminate colitis. Active perianal fistula as the primary symptom. Fibrostenotic disease with primarily obstructive symptoms. Hospitalization within the past 2 weeks. Bowel resection within the past 4 weeks. Subtotal colectomy. Permanent Ileostomy. Is infected with human immunodeficiency virus (HIV; positive serology for HIV antibody). Has a concomitant diagnosis or any history of congestive heart failure or demyelinating disease. Has current signs or symptoms, or a history of severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic, systemic lupus erythematosus, or psychiatric diseases. Has a transplanted organ (except for corneal transplant performed > 3 months prior to screening). Has a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (e.g., nodes in the posterior triangle of the neck, supraclavicular, epitrochlear, or paraaortic areas), or splenomegaly. Has previously undergone allergy immunotherapy for prevention of anaphylactic reactions. Is unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins. Has known allergies, hypersensitivity, or intolerance to ustekinumab or excipients (refer to the ustekinumab prescribing information). Has a clinically significant substance abuse problem (eg, drugs or alcohol) at screening or during the previous 12 months prior to baseline. Any biologic or small molecule therapy within 4 weeks of start of ustekinumab. Positive quantiferon gold that is not being treated and followed by Infectious Disease Tests positive for HBV surface antigen (HBsAg), regardless of the results of other hepatitis B tests. Subjects who test positive only for core antibody (anti-HBc) must undergo further testing for hepatitis B DNA acid (HBV DNA test). If the HBV DNA test is positive, the subject is not eligible for this study. If the HBV DNA test is negative, the subject is eligible for this study. In the event the HBV DNA test cannot be performed, the subject is not eligible for this study. Change in dose of 6-MP, methotrexate, or azathioprine within one month of the start of ustekinumab. Change in prednisone or budesonide dose within 2 weeks of start of ustekinumab Change in mesalamine dosage within 2 weeks of start of ustekinumab Has a stool culture or other examination positive for an enteric pathogen, including Clostridium difficile toxin, in the last 4 months unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen Has received a Bacillus Calmette-Guérin (BCG) vaccination within 12 months or any other live bacterial or live viral vaccination within 2 weeks of baseline. Have immune deficiency syndrome (e.g., severe combined immunodeficiency syndrome, T-cell deficiency syndromes, B-cell deficiency syndromes, and chronic granulomatous disease). Is seropositive for antibodies to hepatitis C (HCV) without a history of clearance or successful treatment, defined as being negative for HCV RNA in the past year and, if treated, at least 24 weeks after completing antiviral treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV Weight-Based Induction Dose<br> | Drug: Ustekinumab<br>* A second IV weight-based induction dose of Stelara at week 8<br>* Other names: Stelara;Drug: Ustekinumab<br>* All patients will receive IV ustekinumab weight-based dose at 260mg (55kg or less), 390mg (more than 55kg to 85kg), or 520mg (more than 85kg) at time point 0<br>* Other names: Stelara;|
| Active Comparator: Standard Subcutaenous Dose<br> | Drug: Ustekinumab<br>* A standard 90mg subcutaneous dose of Stelara at week 8<br>* Other names: Stelara;Drug: Ustekinumab<br>* All patients will receive IV ustekinumab weight-based dose at 260mg (55kg or less), 390mg (more than 55kg to 85kg), or 520mg (more than 85kg) at time point 0<br>* Other names: Stelara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with clinical remission | The Crohn's Disease Activity Index or CDAI is frequently used to assess disease severity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 7 days, and other measurements such as the patient's weight and haematocrit. A CDAI score of less than 150 is considered to be clinical remission. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with a clinical response | A clinical response is defined as a drop in CDAI score by at least 100 points between week 0 and week 16, or a CDAI < 150. | Week 16 | 
| Number of patients with a composite clinical and biomarker response | Defined as a drop in CDAI by at least 100 points from week 0 to week 16, or a CDAI < 150, and a biomarker response (drop in CRP and fecal calprotectin) from week 0 to week 16. | Week 16 | 
| Number of patients with a composite clinical and biomarker remission | Defined as a CDAI < 150 and a CRP <5mg/l or a fecal calprotectin <150 ug/g | Week 16 | 
| Change in Crohn's Disease Activity Index (CDAI) Score | The Crohn's Disease Activity Index or CDAI is frequently used to assess disease severity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 7 days, and other measurements such as the patient's weight and haematocrit. A CDAI score of less than 150 is considered to be clinical remission, a score greater than 220 is considered to define moderate to severe disease, and a score greater than 300 is considered to be severe disease. | Week 0, Week 16 | 
| Number of patients with improvement in health-related quality of life | Defined as increase in SIBDQ by at least 9 points between week 0 and week 16. The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is a 10-item health-related quality of life (HRQoL) questionnaire validated for use in CD patients. It assesses 4 domains: physical, social, emotional, and systemic and is scored on a 7-point Likert scale from 1 (severe problem) to 7 (no problems at all). The absolute score ranges from 10 (poor HRQOL) to 70 (optimum HRQOL). | Week 16 |