| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A chronic inflammatory bowel disease that affects the lining of the digestive tract. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 |
|
| 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 compare the efficacy of treatment with ustekinumab or adalimumab in biologic naïve subjects with moderately-to-severely active Crohn's disease (CD) who have previously failed or were intolerant to conventional therapy (corticosteroids and/or immunomodulators, ie, azathioprine [AZA], 6 mercaptopurine [6-MP], or methotrexate [MTX]), as measured by clinical remission at one year. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the following in biologic naïve subjects with moderately-to-severely active CD treated with ustekinumab or adalimumab:
• Other measures of clinical efficacy (eg, clinical response) including reductions in frequent concomitant medications associated with adverse outcomes (eg steroids, narcotics)
• Anti-inflammatory efficacy assessed with biomarkers (eg, fecal calprotectin, C-reactive protein)
• Endoscopic endpoints (eg, endoscopic remission)
• Safety (eg, proportions of subjects with serious adverse events, all adverse events, etc.)
• CD-related healthcare utilization (eg, CD-related hospitalizations, surgeries, emergency room [ER] visits) and the need to initiate another biologic treatment
• Patient-reported outcome (PRO) assessments, such as Inflammatory Bowel Disease Questionnaire (IBDQ) and Patient Reported Outcome Measurement Information System (PROMIS). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject must meet the following criteria to be enrolled:
1. Be male or female (according to their reproductive organs and functions assigned by chromosomal complement) ≥18 years of age
2. Has CD or fistulizing CD of at least 3 months duration, with colitis, ileitis, or ileocolitis, confirmed at some time in the past by radiography, histology, and/or endoscopy
3. Has moderately-to-severely active CD with a baseline Crohn’s disease activity index (CDAI) score of ≥ 220 and ≤ 450
4. Has one or more ulceration on screening ileocolonoscopy which by definition would result in an Simple Endoscopic Score for Crohn’s Disease (SES-CD) total score of at least 3
Note: If a subject had an ileocolonoscopy but then screen failed for another reason, if he/she is rescreened within 3 months, then that ileocolonoscopy is sufficient for inclusion if all other entry criteria are met
5. Meets the following requirements for prior or current medications for CD:
a) Has failed conventional therapy:
i) Is currently receiving corticosteroids and/or immunomodulators (ie, AZA, MTX, or 6-MP) at adequate therapeutic doses; OR
ii) Has a history of failure to respond to, or tolerate, an adequate course of corticosteroids and/or immunomodulators (ie, AZA, MTX, or 6-MP); OR
iii) Is corticosteroid dependent or has a history of corticosteroid dependency;
AND b) Has not previously received an approved biologic for CD (ie, infliximab, adalimumab, certolizumab pegol, ustekinumab, natalizumab, vedolizumab or approved biosimilars of these agents)
6. Subjects on oral corticosteroids (eg, prednisone, budesonide) at a prednisone-equivalent dose of ≤ 40 milligram (mg)/day or ≤ 9 mg/day of budesonide are permitted provided doses meeting these requirements are stable for 3 weeks prior to baseline (Week 0) or these have been discontinued at least 3 weeks prior to baseline
7. Subjects on the immunomodulators AZA, 6-MP, or MTX at screening (or recently prior), must discontinue these medications at least 3 weeks prior to baseline
8. Has screening laboratory test results within the following parameters:
a) Hemoglobin: ≥ 8.5 gram per decilitre (g/dL)
b) White blood cells (WBC): > 3.5 x 103/microlitre (µL)
c) Neutrophils: >1.5 x 103/µL
d) Platelets: > 100 x 103/µL
e) Serum creatinine: < 1.7 milligram per decilitre (mg/dL)
f) Aspartate transaminase (AST) and alanine transaminase (ALT) concentrations:
Within 2 times the upper limit of normal range for the laboratory conducting the test
g) Direct (conjugated) bilirubin: < 1.0 mg/dL
9. Is considered eligible per the following tuberculosis (TB) screening criteria:
a) Has no history of latent or active TB prior to screening; exceptions are made for a subject who:
• Is currently receiving treatment for latent TB without evidence of active TB (or has initiated treatment for latent TB prior to Week 0 study agent administration)
• Has a history of latent TB and documentation of having completed adequate treatment for latent TB within 5 years prior to the first administration of study agent.
It is the responsibility of the investigator to verify the adequacy of previous TB treatment and provide/obtain appropriate documentation.
b) Has no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c) Has had no recent, known close contact with a person with active TB or, if there has been such contact, the subject is to 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 agent.
d) Within 2 months prior to the first administration of study agent, either has:
• A negative QuantiFERON-TB test, or
• A newly identified positive QuantiFERON-TB test 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 agent.
A subject whose first QuantiFERON-TB test result is indeterminate should have the test repeated. In the event that additional QuantiFERON-TB test result is persistently indeterminate, the subject should also initiate treatment for latent TB in order to enter the study.
The QuantiFERON-TB In-Tube test is not required at screening for subjects with a history of latent TB and appropriate treatment as described above.
e) Has a chest radiograph (at least a posterior-anterior view), taken within 3 months prior to the first administration of study agent and read by a qualified radiologist, with no evidence of current, active TB or old, inactive TB
For a complete overview please refer to the Protocol |
|
| E.4 | Principal exclusion criteria |
A subject who meets any of the following criteria may not be enrolled in the study:
1. Has complications of CD that are likely to require surgery or would confound the ability to assess the effect of ustekinumab or adalimumab treatment using the CDAI, such as: active stoma: short-gut syndrome and severe or symptomatic strictures or stenosis
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 for intra-abdominal abscesses, if 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 present
3. Has had any kind of bowel resection within 6 months prior to baseline or other intra-abdominal surgery or a hospital admission for bowel obstruction within 3 months prior to baseline
4. At any time received any monoclonal antibody (including biosimilars) targeting tumor necrosis factor alfa (TNFα), IL-12, or IL-23, or anti-integrin agents approved for CD (ie, vedolizumab or natalizumab) or has received any of the following medications or therapies within the specified periods prior to baseline:
a) Any other investigational agent for CD (eg other biologics, small molecules or anti-sense ribonucleic acid (RNA) such as mongersen), unless at least 3 months or 5 half-lives have elapsed since last dose
b) Intravenous (IV) corticosteroids as a treatment for CD < 3 weeks prior to baseline
c) Oral immunomodulatory agents other than AZA, 6-MP, or MTX (eg, Janus kinase [JAK] inhibitors, 6-thioguanine [6-TG], cyclosporine, tacrolimus, sirolimus, tofacitinib, or mycophenolate mofetil) < 4 weeks prior to baseline
(Note that per inclusion criterion 7, typical immunomodulator agents [AZA, 6-MP or MTX] must have been discontinued at least 3 weeks prior to baseline.)
d) Treatment with apheresis (eg, Adacolumn apheresis) or total parenteral nutrition (TPN) as a treatment for CD < 3 weeks prior to baseline
5. 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
6. 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
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 nonremitting cystitis), or infected skin wounds or ulcers
8. Has current signs or symptoms of infection, or recent (within 8 weeks prior to baseline) history of herpes zoster or serious infection (including any requiring hospitalization)
Established nonserious infections (eg, acute upper respiratory tract infection, simple urinary tract infection) need not be considered exclusionary at the discretion of the investigator
9. 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
10. 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
11. Has ever had a nontuberculous mycobacterial infection or serious opportunistic infection (eg, cytomegalovirus causing colitis, Pneumocystis jiroveci, aspergillosis)
12. 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. Subjects who test positive for anti-HCV antibodies must undergo further testing for HCV RNA. If the HCV RNA test is
positive the subject is not eligible for this study. If the HCV RNA test is negative, the subject is eligible for this study. In the event the HCV RNA test cannot be performed, the subject is not eligible for this study.
13. 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 the study
For a complete overview please refer to the Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of subjects with clinical remission (defined as a Crohn’s Disease Activity Index [CDAI] score < 150) at Week 52 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Major Secondary Efficacy Endpoints
1. Corticosteroid-free remission at Week 52 (defined as a CDAI score < 150 and not taking any corticosteroids for at least 30 days prior to Week 52)
2. Clinical response (defined as a CDAI score decrease ≥100 from baseline) at Week 52
3. PRO-2 symptom remission at Week 52 (defined as an abdominal pain [AP] mean daily score at or below 1 and also stool frequency [SF] mean
daily score at or below 3, ie, AP≤1 and SF≤3). PRO-2 are the stool frequency and abdominal pain scores reported as part of the CDAI.
4. Clinical remission (defined as CDAI < 150) at Week 16
5. Endoscopic remission (defined as an SES-CD score ≤3, or SES-CD=0 for subjects who enter the study with an SES-CD=3) at Week 52
Secondary Endpoints
6. The proportion of subjects with clinical remission (defined as CDAI < 150), compared at each postbaseline visit through Week 52
7. The proportion of subjects with clinical response (defined as a CDAI score decrease ≥100 from baseline), compared at each postbaseline visit through Week 52
8. The proportion of subjects with durable clinical response at Week 52 (defined as CDAI>100 decrease from baseline at Week 52 and at ≥80% of all visits between Week 16 and Week 52)
9. The proportion of subjects with durable clinical remission at Week 52 (defined as CDAI <150 at Week 52 and at ≥80% of all visits between Week 16 and Week 52)
10. Absence and/or resolution of AP, defined as a mean daily CDAI AP score of 0 in the week prior to the visit among subjects with mean AP >0 at baseline, compared at each postbaseline visit through Week 52
11. Absence and/or resolution of diarrhea, defined as no loose or watery stools in the week prior to the visit (ie, SF CDAI sub-score = 0) among subjects with mean SF >1 at baseline, compared at each postbaseline visit through Week 52
12. The proportion of subjects with clinical and biomarker remission, defined as the proportion of subjects with CDAI<150, CRP <3 mg/L, and also fecal calprotectin ≤250 μg/g, compared at Weeks 8, 16 and 52
13. The proportion of subjects with at least one AE, and subcategories of AEs including infections, SAEs, and serious infections
14. The proportion of subjects with anti-drug antibodies |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Major Secondary Efficacy Endpoints
1, 2, 3 and 5. At Week 52
4. At Week 16
Secondary Endpoints
6, 7, 10 & 11 Through Week 52
8 & 9 At week 52
12 at Weeks 8, 16 and 52
13 & 14 through out the trial |
|
| 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 | Yes |
| 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 |
| Immunogenicity Analyses and Biomarker assessments |
|
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| Korea, Republic of |
| Russian Federation |
| Serbia |
| United States |
| Belgium |
| Bulgaria |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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