| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to severely active Crohn's disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Digestive System and Oral Physiological Phenomena |
|
| 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 | 14.0 |
| 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 |
The primary objectives are:
- To evaluate the efficacy of IV induction regimens of Ustekinumab in inducing clinical response in subjects with moderately to severely active Crohn’s disease who have failed or are intolerant to one or more tumor necrosis factor (TNF) antagonist therapies.
- To evaluate the safety of IV induction regimens of Ustekinumab in subjects with moderately to severely active Crohn’s disease who have failed or are intolerant to one or more TNF antagonist therapies. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
- To evaluate the efficacy of IV induction regimens of Ustekinumab in inducing clinical remission.
- To evaluate the efficacy of IV induction regimens of Ustekinumab in improving disease-specific health-related quality of life.
- To evaluate the pharmacokinetics and pharmacodynamics of Ustekinumab therapy, including changes in C-reactive protein (CRP), fecal calprotectin, fecal lactoferrin, and other pharmacodynamic biomarkers.
- To provide, along with induction study CNTO1275CRD3002, the target study population to be evaluated in the maintenance study CNTO1275CRD3003. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Be a man or woman ≥ 18 years of age.
2. Have Crohn’s disease or fistulizing Crohn’s disease of at least 3 months’ duration, with colitis, ileitis, or ileocolitis, confirmed at any time in the past by radiography, histology, and/or endoscopy.
3. Have active Crohn’s disease, defined as a baseline CDAI score of ≥ 220 and ≤ 450.
4. Have received infliximab, adalimumab, or certolizumab pegol at a dose approved for the treatment of Crohn’s disease and
a. Did not respond initially;
OR
b. Responded initially but then lost response with continued therapy;
OR
c. Were intolerant to the medication.
5. Adhere to the following requirements for concomitant medication for the treatment of Crohn’s disease. 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-ASA compounds.
b. Oral corticosteroids at a prednisone-equivalent dose of ≤ 40 mg/day or ≤ 9 mg/day of budesonide.
c. Antibiotics being used as a primary treatment of Crohn’s disease.
d. Subjects receiving conventional immunomodulators must have been taking them for ≥ 12 weeks, and on a stable dose for a least 4 weeks prior to baseline.
6. Have screening laboratory test results within the parameters mentioned in the protocol:
7. Are considered eligible according to the following TB screening criteria:
a. Have no history of latent or active TB prior to screening. Exceptions are made for subjects currently receiving treatment for latent TB, if there is no evidence of active TB, or who have a history of latent TB and documentation of having completed adequate treatment for latent TB within 3 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 appropriate documentation.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c. 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 agent.
d. Within 2 months prior to the first administration of study agent, either have negative QuantiFERON-TB Gold test, or have a newly identified positive QuantiFERON-TB Gold 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 negative tuberculin skin test is additionally required if the QuantiFERON-TB gold test is not approved/registered in that country. The QuantiFERON-TB Gold In-Tube test is not required at screening for subjects with a history of latent TB and appropriate treatment as described in 7a.
e. Have a chest radiograph, 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.
8. If a woman, before entry she must be:
a. Postmenopausal, defined as
1) > 45 years of age with amenorrhea for at least 18 months,
OR
2) > 45 years of age with amenorrhea for at least 6 months and a serum follicle stimulating hormone (FSH) level > 40 IU/mL
OR
b. Menstrual
1) Surgically sterile, or
2) 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, or male partner sterilization, consistent with local regulations regarding use of birth control methods for subjects participating in clinical trials, for the duration of their participation in the study and for 20 weeks after receiving study agent, or
3) Not heterosexually active.
9. If a woman of childbearing potential, she must have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening; and a negative urine pregnancy test at Week 0.
10. If a man and heterosexually active with a woman of childbearing potential, he must agree to use a double barrier method of birth control and to not donate sperm during the study and for 20 weeks after receiving study agent.
11. Be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
12. Sign an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study, and intend to participate in the maintenance study if eligible. |
|
| E.4 | Principal exclusion criteria |
1. Has complications of Crohn’s disease such as symptomatic strictures or stenoses, short gut syndrome, or any other manifestation that might be anticipated to require surgery, could preclude the use of the CDAI 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 that 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 had any kind of bowel resection within 6 months or any other intra-abdominal surgery within 3 months prior to baseline.
4. Has a draining stoma or ostomy.
5. Has received any of the prescribed medications or therapies within the specified period (mentioned in the protocol).
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 previously received a biologic agent targeting IL-12 or IL-23, including but not limited to ustekinumab (CNTO 1275) or briakinumab (ABT-874).
8. 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.
9. 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, or open, draining, or infected skin wounds or ulcers.
10. Has current signs or symptoms of infection. Established nonserious infections need not be considered exclusionary at the discretion of the investigator.
11. Has a history of serious infection, including any infection requiring hospitalization or IV antibiotics, for 8 weeks prior to baseline.
12. Has evidence of a herpes zoster infection ≤ 8 weeks prior to baseline.
13. 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.
14. Has evidence of current active infection, including but not limited to TB (exceptions see protocol).
15. Has or ever has had a nontuberculous mycobacterial infection or serious opportunistic infection.
16. Is known to be infected with HIV, hepatitis B, or hepatitis C.
17. Has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof.
18. Has a transplanted organ.
19. Has a known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
20. Has any known malignancy or has a history of malignancy.
21. Has previously undergone allergy immunotherapy for prevention of anaphylactic reactions.
22. Is unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins.
23. Is known to have had a substance abuse problem within the previous 12 months prior to baseline.
24. Has known allergies, hypersensitivity, or intolerance to ustekinumab or its excipients.
25. Are currently or intending to participate in any other study using an investigational agent or procedure during participation in this study.
26. Is a woman who is pregnant, or breast-feeding, or planning to become pregnant or is a man who plans to father a child while enrolled in this study or within 20 weeks after the last dose of study agent.
27. Has any condition that, in the opinion of the investigator, would make participation not be in the best interest of the subject or that could prevent, limit, or confound the protocol-specified assessments. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is clinical response at Week 6, defined as a reduction from baseline in the CDAI score of ≥ 100 points. Subjects with a baseline CDAI score of ≥ 220 to ≤ 248 points are considered to be in clinical response if a CDAI score of < 150 is attained. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The major secondary endpoints, in order of importance, are:
1. Clinical remission at Week 8, defined as a CDAI score of < 150 points.
2. Clinical response at Week 8.
3. 70-point response at Week 6, defined as a reduction from baseline in the CDAI score of ≥ 70 points.
4. 70-point response at Week 3. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 |
| European Union |
| Australia |
| Brazil |
| Canada |
| Iceland |
| Israel |
| Japan |
| Korea, Republic of |
| New Zealand |
| Serbia |
| South Africa |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
Subjects entering maintenance study CNTO1275CRD3003 will be considered to have completed induction study CNTO1275CRD3001 if they’ve completed the Week 8 visit.
Subjects not entering maintenance study CNTO1275CRD3003 will be considered to have completed induction study CNTO1275CRD3001 if they’ve completed the safety follow up visit approximately 20 weeks after study agent administration at Week 0. |
|
| 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 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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