| 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 |
|
| 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 | 17.0 |
| 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 |
|
| 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 doses. |
|
| 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. |
|
| 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 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 (eg,
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 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 (e.g., 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.
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.
|
|
| E.4 | Principal exclusion criteria |
1.Diagnosis of indeterminate colitis, UC, or clinical findings suggestive of
UC. 2.Subjects diagnosed with Crohn's disease but without previous
exposure to treatment or having failed or been intolerant to treatment
solely with 5 ASA containing compounds. 3.Subjects receiving treatment
for Crohn's disease (see protocol for list of treatments). 4.Other
investigational or marketed biologics with immunomodulatory properties
within 3 months prior to baseline. 5.Subjects who have previously
received natalizumab, or any anti adhesion molecule, within 1 year prior
to baseline. 6.Leukocyte apheresis including selective lymphocyte,
monocyte, or granulocyte apheresis, or plasma exchange within 6
months. 7.Subjects who have previously participated in any study of
tofacitinib. 8.Participation in other interventional clinical studies within 3
months prior to baseline and/or during study. 9.History of symptomatic obstructive strictures unless the stricture has been surgically treated or treated with dilation without recurrence of symptoms for at least 6 months 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 (>100 cm) or short bowel syndrome. 11.History of
bowel surgery within 6 months prior to baseline. 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, intra-abdominal or perineal collection or abscess.15.Subjects on elemental diet used for treating
Crohn's disease within 7 days from baseline. 16.Subjects with blood
dyscrasias at screening. 17.Subjects with evidence of or suspected liver
disease eg, liver injury due to methotrexate 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 1.5 times the upper limit of normal at screening.
20.Subjects with current or recent history of severe, progressive, or
uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic,
endocrine, pulmonary, cardiac, or neurological disease. 21.Subjects who
have been vaccinated with any live or attenuated virus vaccine within 6
weeks of baseline or scheduled to receive live virus vaccination during
study period and for 6 weeks after last dose of study drug. 22.Subjects
with history of any lymphoproliferative disorder, history of lymphoma,
leukemia, myeloproliferative disorders, multiple myeloma, or signs and
symptoms suggestive of current lymphatic disease. 23.Subjects with
clinically significant infections currently or within 6 months of baseline,
a history of any infection requiring antimicrobial therapy within 2 weeks
of baseline, or a history of any infection otherwise judged by the
investigator to have the potential for exacerbation by participation in the
study. 24.Subjects with a history of more than one episode of herpes
zoster, a history of disseminated herpes zoster 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 1 year 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 6
months of abstinence prior to baseline. 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 500 mL within 8 weeks prior to baseline.
31.Subjects with history of blood transfusion within 4 weeks prior to
baseline. 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 4 weeks of screening visit. 35.Subjects
infected with HIV 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. See Protocol
for additional criteria and details.
|
|
| 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. |
|
| 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 |
|
| 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. |
|
| 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
|
|
| 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
| 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 | 4 |
| 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 |
| Australia |
| Austria |
| Bulgaria |
| Canada |
| Croatia |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Japan |
| Korea, Republic of |
| Netherlands |
| South Africa |
| Spain |
| Ukraine |
| 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
|
| 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. |
|
| 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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