| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011402 |
| E.1.2 | Term | Crohn's disease (colon) |
| E.1.2 | System Organ Class | 100000004856 |
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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 |
| The primary objective of the study is to evaluate the dose-response of tofacitinib in inducing clinical remission in subjects with moderate to severe Crohn’s disease and to select effective dose. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of tofacitinib induction therapy in subjects with moderate to severe Crohn’s disease.
To evaluate the dose-response of tofacitinib in inducing clinical response in subjects with moderate to severe Crohn’s disease.
To characterize the pharmacokinetics of tofacitinib in subjects with moderate to severe Crohn’s disease.
To evaluate the effect of tofacitinib on quality of life in subjects with moderate to severe Crohn’s disease.
To evaluate the effect of tofacitinib on CRP and fecal calprotectin. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study. Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Male or female subjects between the ages of ≥18 and ≤75 years at screening.
2. Subjects with documented clinical diagnosis of Crohn’s disease (CD) for at least 6 months prior to screening.
3. Subjects with active moderate to severe ileal, ileocolic, or colonic CD defined by a baseline score of Crohn’s Disease Activity Index (CDAI) of ≥220 to ≤450 at baseline.
4. Subjects with a history of inadequate treatment response or intolerance (as defined by the Investigator) to at least one of the following therapies for Crohn’s disease:
• Corticosteroids.
• Azathioprine/6-Mercaptopurine.
• Methotrexate.
• Anti-TNF therapy (Infliximab; Adalimumab; Certolizumab pegol).
5. Subjects currently receiving any of the following treatments for Crohn’s disease are eligible provided they are on stable dose for designated period of time and throughout the study:
• Oral 5-ASA or sulfasalazine stable dose for at least 4 weeks prior to baseline.
• Oral corticosteroids (prednisolone up to 30 mg/day; budesonide up to 9 mg/day) stable dose for at least 2 weeks prior to baseline.
• Chronic treatment for Crohn’s disease with antibiotics (e.g. metronidazole, rifaximin) stable dose for at least 2 weeks prior to baseline.
• Rectally administered formulation of corticosteroids or 5-ASA stable dose for at least 2 weeks prior to baseline.
• Seton placement before enrollment must remain in place during the study
6. Subjects with presence of ulceration at screening/baseline colonoscopy as documented by the Simple Endoscopic Score for Crohn’s Disease (SES-CD): aphthous ulcers (0.1 to 0.5 cm), large ulcers (0.5 to 2 cm), or very large ulcers (>2 cm).
7. No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by all of the following:
•A negative QuantiFERON-TB Gold (QFT-G) In-Tube test documented within 3 months prior to or during screening. If initial and repeat QFT-G tests are indeterminate, a negative Mantoux Purified Protein Derivative (PPD) tuberculin skin test (with a result of <5 mm of induration), documented within 3 months prior to or during screening is required. [Subjects with a history of Bacille Calmette Guérin (BCG) vaccination must have a negative QFT-G test.].
• A chest radiograph taken at or within the 3 months prior to screening, without changes suggestive of active TB infection as determined by a qualified radiologist.
• No history of either untreated or inadequately treated latent or active TB infection.
• If a subject has previously received an adequate course of therapy for either latent (eg.9 months of isoniazid in a locale where rates of primary multi-drug resistant TB infection are <5% or an acceptable alternative regimen) or active (acceptable multi-drug regimen) TB infection, neither a PPD test nor a QFT G test is needed, but a negative chest radiograph must still be obtained if not performed within 3 months prior to screening. Documentation of adequate treatment for TB will be obtained prior to first dose of study drug.
• A subject who is currently being treated for active TB infection is to be excluded.
• A subject who is currently being treated for latent TB infection can only be enrolled with confirmation of current incidence rates of multi-drug resistant TB infection in the locale, documentation of an adequate treatment regimen, and with prior approval by the Sponsor.
8. Women of childbearing potential must test negative for pregnancy prior to study enrolment.
9. Sexually active females of childbearing potential are required to use adequate contraceptive methods during the study period and until completion of the follow-up procedures. (Further description of the requirements and a list of contraceptives considered effective and acceptable for use in this trial are found in Section 4.4 Life Style
Guidelines in the protocol).
10. Subjects receiving non-prohibited concomitant medications for any reason, must be on a stable regimen, which is defined as not starting a new medication or changing dosage of a current medication within 7 days or 5 half-lives (whichever is longer) prior to baseline.
11. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
12. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
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| E.4 | Principal exclusion criteria |
1.Diagnosis of indeterminate colitis,ulcerative colitis (UC),or findings suggestive of UC.2.Subjects diagnosed with CD but without prior exposure to treatment (i.e treatment-naïve) or having failed or been intolerant to treatment solely with 5-ASA containing compounds.3.Subjects receiving treatment for CD (see protocol for the list of treatments)4.Other investigational or marketed biologics withimmunomodulatory properties within 3months prior to baseline. 5.Subjects who have previously received natalizumab or any anti-adhesion molecule, within 1year PTB. 6.Leukocyte apheresis including selective lymphocyte, monocyte, or granulocyte apheresis,or plasma exchange within 6months. 7.Subjects who have previously participated in any study of tofacitinib. 8.Participation in other interventional clinical studies within 3months PTB/or during study. 9.History of symptomatic obstructive strictures unless the stricture has been surgically treated with dilation without recurrence of symptoms for at least 6months prior to enrollment or an active ostomy. 10.History of total colectomy or subtotal colectomy to the extent that it precludes the subject from having any formed stool,extensive small bowel resection(>100cm) or short bowel syndrome.11.History of bowel surgery within 6months PTB. 12.Subjects likely to require any type of surgery during the study period.13.Fecal culture/toxin assay indicating presence of pathogenic infection.14.Presence of active (draining) fistulae, intrabdominal or perineal collection or abscess (Subjects with prior history of fistulae including entero-cutaneous, entero-enteric, entero-vesicular,entero-vaginal, or perineal fistulae or abdominal or perineal abscess will require MRI of abdomen/pelvis prior to randomization) 15.Subjects on elemental diet used for treating CD within 7days PTB. 16.Subjects with blood dyscrasias at screening 17.Subjects with evidence of or suspected liver disease i.e. liver injury due to MTX or primary sclerosing cholangitis.18.Subjects with estimated GFR ≤40 ml/min at screening, based on Cockcroft-Gault calculation. 19.Subjects with total bilirubin,AST or ALT more than 1.5times upper limit of normal at screening.20.Subjects with current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, GI,metabolic, endocrine, pulmonary, cardiac or neurological disease.21.Subjects who have been vaccinated with any live or attenuated virus vaccine within 6weeks PTB or scheduled to receive live virus vaccination during study period &for 6weeks after last dose of study drug. 22.Subjects with history of any lymphoproliferative disorder, history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs& symptoms suggestive of current lymphatic disease. 23.Subjects with clinically significant infections currently or within 6months PTB, a history of any infection requiring antimicrobial therapy within 2weeks PTB or history of any infection otherwise judged by the investigator to have potential for exacerbation by participation in study. 24.Subjects with a history of more than one episode of herpes zoster (HZ), a history of disseminated HZ or disseminated herpes simplex. 25.Subjects with prior treatment with lymphocyte-depleting agents/therapies. Subjects who have received rituximab or other selective B lymphocyte depleting agents are eligible if they have not received such therapy for at
least 1year prior to baseline 26.Subjects with any condition possibly affecting oral drug absorption. 27.Women who are pregnant or breastfeeding,or planning pregnancy during the study period. 28.History of alcohol or drug abuse with less than 6months of abstinence PTB. 29.Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results. 30.Subjects with history of blood donation in excess of 500mL within 8weeks PTB. 31.Subjects with history of blood transfusion within 4weeks PTB. 32.Subjects with a first-degree relative with a hereditary immunodeficiency. 33.Subjects with any malignancies or with a history of malignancies with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin. 34. Significant trauma or major surgery within 4weeks of screening visit. 35.Subjects infected with human immunodeficiency virus or hepatitis B or C viruses. 36.Subjects receiving prohibited concomitant medications including medications that are either moderate to potent CYP3A4 inducers or inhibitors in the specified time periods prior to the first dose of study drug or are expected to receive any of these medications during the study period.
· For moderate to potent CYP3A inducers, within 28days or 5half-lives, whichever is longer, prior to first dose of study drug; ·For moderate to potent CYP3A inhibitors, within 7days or 5half-lives, whichever is longer, prior to first dose of study drug. See protocol for additional criteria and details |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The proportion of subjects in clinical remission at week 8 as defined by a Crohn’s disease
activity index (CDAI) score of less than 150 points. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The proportion of subjects in clinical remission at week 8 as defined by a Crohn’s disease activity index (CDAI) score of less than 150 points |
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| E.5.2 | Secondary end point(s) |
The proportions of subjects in clinical remission (CDAI<150) at Week 2 and 4.
The proportion of subjects achieving clinical response-70 at Week 2, 4, and 8 as defined by a decrease in CDAI score of at least 70 points from baseline.
The proportion of subjects achieving clinical response-100 at Week 2, 4, and 8 as defined by a decrease in CDAI score of at least 100 points from baseline.
The proportion of subjects achieving either clinical response-100 or clinical remission (CDAI<150) at Week 2, 4, and 8.
CDAI scores over time.
Serum CRP and fecal calprotectin levels over time.
Plasma tofacitinib concentration over time. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The proportions of subjects in clinical remission (CDAI<150) at week 2 and 4
The proportion of subjects achieving clinical response-70 at week 2, 4, and 8 as defined by a decrease in CDAI score of at least 70 points from baseline
The proportion of subjects achieving clinical response-100 at week 2, 4, and 8 as defined by a decrease in CDAI score of at least 100 points from baseline
The proportion of subjects achieving either clinical response-100 or clinical remission (CDAI<150) at week 2, 4, and 8
CDAI scores over time
Serum CRP and fecal calprotectin levels over time
Plasma tofacitinib concentration over time
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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 | No |
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Bulgaria |
| Canada |
| France |
| Greece |
| Japan |
| Austria |
| Croatia |
| Netherlands |
| Norway |
| Slovakia |
| Sweden |
| Australia |
| Czech Republic |
| Germany |
| Hungary |
| Korea, Republic of |
| Spain |
| Israel |
| South Africa |
| Ukraine |
| United States |
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| 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
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| EOT in all participating countries is defined as LSLV. EOT in a Member State of the EU is defined as time at which it is deemed that sufficient subjects have been recruited & completed the study as stated in regulatory application (ie, Clinical Study Application) ðics application in the Member State (MS). Poor recruitment (recruiting less than the anticipated number in the CTA) by a MS is not a reason for premature termination but is considered a normal conclusion to the study in that MS. |
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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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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