| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011401 |
| E.1.2 | Term | Crohn's disease |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the real world effectiveness of ustekinumab (routine care) as combined clinical and endoscopic response in week 52. |
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| E.2.2 | Secondary objectives of the trial |
- to examine the robustness of the primary endpoint analysis, sensitivity analyses of the primary endpoint will be conducted.
Evaluate the real world effectiveness (routine care):
- in achieving and maintaining endoscopic remission.
- in improving endoscopic and clinical indexes.
- in achieving and maintaining of mucosal healing.
- in achieving and maintaining clinical remission.
- in achieving and maintaining steroid free clinical remission.
- in achieving and maintaining clinical response.
- in controlling perianal disease activity in subjects with active fistulizing Crohn’s disease at baseline
- on serum CRP and albumin, as well as fecal calprotectin levels.
- on health-related quality of life and patient-reported outcomes (PRO-2 soft stool frequency over past week abdominal pain over past week)
- on extraintestinal manifestations and/or phenotype
- describe the safety of real world ustekinumab use at every study visit |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female ≥18 years of age
2. Have active, moderate to severe, ileal and/or colonic CD, demonstrated by: HBI score of ≥ 5 at Baseline; Endoscopy with evidence of active CD (defined as SES-CD score ≥3 excluding the contribution of the narrowing component score) obtained within the 2-week screening period. A prior endoscopy may be used only if obtained within 3 months prior to baseline (Week 0), in which case the prior endoscopy must be centrally read again and SES-CD calculated based on this second, centralized read-out.
3. Has had an inadequate response with, lost response to, was intolerant to, or had medical contraindications to one or more previous biologic therapies approved for the treatment of CD in Germany (ie, infliximab, adalimumab or vedolizumab) or had an inadequate response to conventional therapy (no biological treatment).
4. Adhere to the following requirements for concomitant medication for the treatment of CD. The following medications are permitted provided doses meeting the requirements below are stable for or have been discontinued at least 3 weeks prior to baseline (Week 0), unless otherwise specified:
a. Oral 5-aminosalicylic acid (5-ASA) compounds; b. Oral corticosteroids (eg, prednisone, budesonide) at a prednisone-equivalent dose of ≤40 mg/day or ≤9 mg/day of budesonide. Subject must be willing to taper corticosteroids; c. Antibiotics being used as a primary treatment of CD; d. Conventional immunomodulators (ie, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]). Subjects must have been taking them for≥12 weeks, and on a stable dose for a least 4 weeks prior to baseline.
5. Are eligible according to tuberculosis (TB) infection screening criteria.
6. Must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
7. A woman of childbearing potential must have a negative highly sensitive serum (β -human chorionic gonadotropin [β-hCG]) pregnancy test at screening, and a negative urine pregnancy test at Week 0.
8. Contraceptive use by men or women should be consistent with German Federal or State regulations regarding the use of contraceptive methods for subjects participating in clinical studies. Before inclusion, a woman must be either: a. Not of childbearing potential defined as: Premenarchal; Postmenopausal (A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level) (>40 IU/L or mIU/mL) in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy, however in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Permanently sterile (Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy.)
b. Of childbearing potential and: practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly). Examples of highly effective contraceptives included in protocol (page 27); agrees to remain on a highly effective method throughout the study and for at least 15 weeks after the last dose of ustekinumab. Note: If the childbearing potential changes after the start of the study or the risk of pregnancy changes (eg, a woman who is not heterosexually active becomes active,) a woman must begin a highly effective method of contraception, as described throughout the inclusion criteria.
9. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 15 weeks after the last ustekinumab administration.
10. During the study and for 15 weeks after receiving the last dose of ustekinumab, in addition to a highly effective method of contraception, a man
• who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository)
• must agree not to donate sperm.
11. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
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| E.4 | Principal exclusion criteria |
1. Has complications of CD such as symptomatic strictures or stenoses, short bowel syndrome, or any other manifestation that might be anticipated to require immediate surgery, could preclude the use of the HBI to assess response to therapy, or would possibly confound the ability to assess the effect of treatment with ustekinumab.
2. Currently has or is suspected to have an abscess. Recent cutaneous and perianal abscesses are not exclusionary if drained and adequately treated at least 3 weeks prior to baseline, or 8 weeks prior to baseline for intra-abdominal abscesses, provided there is no anticipated need for any further surgery. Subjects with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses identified.
3. Has previously received a biologic agent targeting IL-12 and/or IL-23, including but not limited to ustekinumab.
4. Has received any of the following prescribed medications or therapies within the specified period: a. Non-autologous stem cell therapy or biologic agents that deplete B or T cells <12 months prior to baseline.
b. Any investigational drug within 4 weeks before first administration of ustekinumab or within 5 half-lives of the investigational drug, whichever is longer.
5. Has received a Bacille Calmette-Guérin (BCG) vaccination within 12 months or any other live bacterial or live viral vaccination within 12 weeks of baseline.
6. Have 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.
7. Has a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection, recurrent urinary tract infection (eg, recurrent pyelonephritis or chronic non-remitting cystitis), or open, draining, or infected skin wounds or ulcers.
8. Has current signs or symptoms of infection. Established non-serious infections (eg, acute upper respiratory tract infection, simple urinary tract infection) need not be considered exclusionary at the discretion of the investigator.
9. Has a history of serious infection (eg, sepsis, pneumonia, or pyelonephritis), including any infection requiring hospitalization or IV antibiotics, for 8 weeks prior to baseline.
10. Has any contraindication according to the German ustekinumab label.
11. Has evidence of a herpes zoster infection ≤8 weeks prior to baseline.
12. Has a history of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, prior to screening. Refer to inclusion criteria for information regarding eligibility with a history of latent TB.
13. Has evidence of current active infection, including TB, or a nodule suspicious for lung malignancy on screening or any other available chest radiograph, unless definitively resolved surgically or by additional imaging and with source document confirmation.
14. Has or ever has had a nontuberculous mycobacterial infection or serious opportunistic infection (eg, cytomegalovirus colitis, Pneumocystis carinii, aspergillosis).
15. Is known to be infected with HIV, hepatitis B, or hepatitis C. Testing at screening is mandatory and must be documented.
16. Has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof.
17. Has a known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
18. Has any known malignancy or has a history of malignancy (with the exception of 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).
19. Has previously undergone allergy immunotherapy (administration of an antigen) for prevention of anaphylactic reactions.
20. Has known allergies, hypersensitivity, or intolerance to ustekinumab or its excipients, or an allergy to latex (refer to the German label “Fachinformation”).
21. Is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 15 weeks after the last dose of ustekinumab
22. Is a man who plans to father a child while enrolled in this study or within 15 weeks after the last dose of ustekinumab.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinical response (Harvey Bradshaw index score reduction ≥ 3 points from baseline) AND endoscopic response (50% reduction of SES-CD from baseline) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- Sensitivity analysis of the clinical response (Harvey Bradshaw index score reduction ≥ 3 points from baseline) AND endoscopic response (50% reduction of SES-CD from baseline)
- Endoscopic remission defined as a SES-CD score ≤2 at Week 26 (optional) and Week 52
- Changes in score from baseline for the Harvey Bradshaw index and SES-CD questionnaire at Weeks 26 and 52.
- Mucosal healing defined as the complete absence of mucosal ulcerations in any ileocolonic segment at Week 26 and Week 52
- Clinical remission as defined by a Harvey Bradshaw index score of ≤ 4. It will be assessed at Weeks 8, 16, 26, 36, 52.
- Steroid free clinical remission as defined by a Harvey Bradshaw index score of ≤ 4and the absence of concomitant steroid therapy in subjects who were on steroids at baseline. It will be assessed at Weeks 8, 16, 26, 36, 52.
- Clinical response as defined as a Harvey Bradshaw index score reduction ≥ 3 points. It will be assessed at Weeks 8, 16, 26, 36, 52.
- The PDAI will be used. Fistula response (yes / no) and remission (yes / no) will be assessed compared with baseline reading. 0 = remission. <4 (inactive disease not requiring therapy) ≥4 (active disease requiring medical or surgical therapy).
- Serum CRP
- Serum albumin
- Fecal Calprotectin on Weeks 0, 8, 16, 26, 36, 52
- Changes from baseline for European quality of life 5 dimensions 5 level (EQ-5D-5L) on Weeks 0, 8, 16, 26, 36, 52
- PRO-2: remission, mild, moderate, severe (<8, 8–13, 14–34, >35) on Weeks 0, 8, 16, 26, 36, 52
- Phenotype according to Montreal classification will be recorded on Weeks 0, 8, 16, 26, 36, 52
- Presence and activity of extraintestinal manifestations will be recorded on Weeks 0, 8, 16, 26, 36, 52
- Adverse events according to MedDRA terminology
- Clinical laboratory data
- Vital signs
- Physical examination findings on Weeks 0, 8, 16, 26, 36, 52.
- Record steroid tapering dose at all visits with concomitant medications
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 0, 8, 16, 26, 36, 52 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Real world effectiveness (routine care) |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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