NIH Substudy of AIN457 (Anti-IL-17 Monoclonal Antibody) for Treatment of Moderate to Severe Crohn's Disease
NIH Substudy of AIN457 (Anti-IL-17 Monoclonal Antibody) for Treatment of Moderate to Severe Crohn's Disease
The objective of this NIH-specific substudy is immunologic monitoring of cytokine and immune
 cell responses in subjects undergoing treatment with AIN457 (human monoclonal anti-human
 interleukin-17A) for moderate to severe Crohn's disease. Recent data suggests that
 interleukin-17 (IL-17) is an important mediator of inflammation in certain animal models of
 Crohn's disease, and treatment aimed at blocking the IL-23-IL-17 axis can ameliorate the
 inflammatory changes. In addition, elevated expression of IL-l7 has been found in the gut
 tissue of patients with active Crohn's disease. This substudy will measure changes in
 cytokine production, relevant RNA expression, and immune cell populations (in the periphery
 and lamina propria) for correlation with clinical outcomes in order to explore the mechanisms
 of therapeutic response.
Purpose:

 -  Crohn's disease is an inflammatory bowel disease with major symptoms such as diarrhea
 and abdominal pain when the disease is in an active stage.

 -  AIN457 is a protein developed by NOVARTIS that is used to stop the action of
 Interleukin-17 (IL-17), a protein made by the body that contributes to many different
 kinds of inflammatory diseases, including Crohn's disease. AIN457 is being developed for
 the potential treatment of various inflammatory diseases like rheumatoid arthritis and
 psoriasis, but has not been tested for suitability in people with Crohn's disease.

 Objectives:

 -  The main objective of the NIH substudy is to obtain additional blood and gut biopsy
 tissue for monitoring biochemical changes in immune variables in response to study drug
 or placebo.

 -  The main objective of the main multicenter study (sponsored by NOVARTIS) is to determine
 whether AIN457 is safe and effective in the treatment of Crohn's disease, and if
 effective, how long the effect will remain.

 Eligibility:

 - Important eligibility criteria to consider for patients to be enrolled in the AIN457 trial
 include:

 Inclusion criteria:

 -  Male or female; 18-75 years old

 -  Diagnosis of Crohn's disease for at least 3 months prior to screening

 -  Moderate to severe active Crohn's disease at baseline, defined as: CDAI greater than or
 equal to 220 and less than or equal to 450

 -  Active disease despite prior treatment with stable dose of corticosteroids for 2 weeks,
 or immunosuppressant for at least 3 months (e.g. methotrexate, azathioprine).

 Exclusion criteria:

 -  Subjects with symptoms associated with active bowel stricturing disease and pre-stenotic
 dilation on radiography.

 -  Fistulizing disease if complicated by sepsis and/or untreated abscess.

 -  Subjects with multiple bowel surgeries and clinically important short bowel syndrome
 defined as an inability to maintain caloric intake.

 -  Prior therapy with rituximab.

 -  Receiving corticosteroids dose equivalent to a > 40mg dose of prednisone per day.

 -  Subjects demonstrating clinical improvement due to other Crohn's therapy.

 -  Subjects with active or history of clinically significant cardiac abnormalities.

 Design:

 -  For the NIH substudy, additional blood will be drawn and a colonoscopy will be performed
 before the first infusion and after the second infusion.

 -  The multicenter study plans to enroll seventy-two (72) subjects with moderate to severe
 active Crohn's disease that is not controlled by corticosteroids, immunosuppressant
 (e.g. methotrexate or purine metabolites) or anti-inflammatory treatment (e.g. 5-ASA).
 At baseline visit, if the eligibility of the subject is confirmed, the subject will be
 randomized (2:1 ratio) to receive either AIN457 or placebo administered as a 2 hours
 intravenous infusion. A total of two infusions will be given on day 1 and day 22
 respectively.

 -  After infusions there will be a follow-up period of up to 18 weeks.

 -  Once this study is completed, an extension study will be conducted that will offer
 access to AIN457. Patients who complete the current study may be eligible to enter the
 extension study and receive therapy with AIN457.
-  INCLUSION CRITERIA:

 1. Male or female; 18-75 years old

 2. All female subjects must have negative pregnancy test results at screening and
 baseline. Women of childbearing potential (WoCBP) must be using simultaneously
 double-barrier or two acceptable methods of contraception, (e.g., intra-uterine
 device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.
 Hormone replacement as either oral or implantable is acceptable as one form),
 from the time of screening and for the duration of the study, through study
 completion and for 4 months following study completion.

 Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation
 methods) and withdrawal are not acceptable methods of contraception.

 Postmenopausal females must have had no regular menstrual bleeding for at least
 two (2) years prior to initial dosing. Menopause will be confirmed by a serum FSH
 level of > 40 IU/L at screening. Pregnancy test will be required only at
 screening.

 Female subjects who report surgical sterilization must have had the procedure at
 least six (6) months prior to initial dosing. Surgical sterilization procedures
 should be supported with clinical documentation made available to the sponsor and
 noted in the Relevant Medical History/Current Medical Conditions section of the
 CRF.

 If female subjects have male partners who have undergone vasectomy, the vasectomy
 must have occurred more than six (6) months prior to first dosing.

 3. Male subjects willing to use simultaneously two acceptable methods of
 contraception (e.g. spermicidal gel plus condom) for entire duration of the
 study, up to the study completion visit and at least for 6 months following the
 completion of the study.

 Periodic abstinence and withdrawal are not acceptable methods of contraception.

 4. Diagnosis of Crohn's disease for at least 3 months prior to screening

 5. Confirmation of Crohn's disease by endoscopic or imaging examination

 6. Moderate to severe active Crohn's disease at baseline, defined as:

 --CDAI greater than or equal to 220 and less than or equal to 450

 7. Patients with active disease despite prior treatment with corticosteroids for at
 least 2 weeks, or immunosuppressants for at least 3 months.

 -  Patients who are being treated with azathioprine, 6-MP or MTX are eligible
 but must have been on a stable dose for at least 10 weeks prior to baseline.

 -  Patients treated with corticosteroids are eligible but must have been on
 stable doses of prednisolone not exceeding 40 mg for two weeks prior to
 baseline.

 -  Patients who are being treated with immunosuppressants other than those
 listed above, such as cyclosporine, tacrolimus and mycophenolate, are not
 eligible. These subjects will be required to stop immunosuppressants prior
 to baseline. These patients are eligible after observing a wash out period
 as specified in Exclusion criterion #7.

 8. Absence of clinically relevant abnormalities for screening laboratory test
 results

 9. Able to communicate well with the investigator, and to understand and comply with
 the requirements of the study.

 10. Understand and sign the written informed consent.

 EXCLUSION CRITERIA:

 Subjects meeting any of the following criteria will be excluded from entry into or
 continuation in the study, unless sponsor approval is obtained:

 1. Body Mass Index is greater than 34.

 2. Positive Purified Protein Derivative (PPD) tuberculin skin test of greater than or
 equal to 5 mm at screening or 6 months prior to screening. A positive PPD test will be
 defined using the [MMWR 2000 guidance], summarized as criteria for tuberculin
 positivity by risk group.

 -  A PPD test should not be done in subjects who had a tuberculosis vaccination in
 the past. These subjects will be eligible to participate if, according to local
 guidelines, latent tuberculosis can be excluded.

 -  For those study sites using QuantiFeron test a positive test at screening will
 exclude the subject from the participation in the study.

 -  If the result for either PPD or QuantiFeron test is indeterminate, the subject
 will be excluded.

 3. Subjects with symptoms associated with active bowel stricturing disease and
 pre-stenotic dilation on radiographs.

 4. Fistulizing disease if complicated by sepsis and/or untreated abscess.

 5. Subjects with multiple bowel surgeries and clinically important short bowel syndrome
 defined as an inability to maintain caloric intake.

 6. a. Concomitant treatment with anti-TNF-alpha therapy (or other biological therapy) and
 systemic immunosuppressive agents such as cyclosporine, mycophenolate, pimecrolimus,
 or tacrolimus, except azathioprine, its metabolite 6-MP and MTX.

 The following washout period will be required for subjects to be eligible to
 participate in the trial.

 -  Three (3) months washout prior to baseline for certolizumab

 -  Two (2) months washout prior to baseline for adalimumab, etanercept and
 infliximab

 -  One (1) month washout prior to baseline for cyclosporine, mycophenolate,
 pimecrolimus, tacrolimus, and any other systemic immunosuppressants not listed
 under exclusion criterion # 7b

 6b. Patients who are being treated with azathioprine, 6-MP or MTX are eligible
 but must have been on a stable dose for at least 10 weeks prior to baseline and
 throughout the whole study period.

 7. Prior therapy with rituximab.

 8. Receiving corticosteroid dose equivalent to a greater than 40mg dose of prednisone per
 day.

 9. Subjects demonstrating clinical improvement due to other Crohn's therapy.

 10. Current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic,
 hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral,
 psychiatric, or other disease which would make the subject unsuitable for the trial.

 11. Subjects with active or history of clinically significant cardiac abnormalities, for
 example:

 -  Requiring drugs with QT-prolonging properties (e.g. antiarrhythmic drugs, such as
 amiodarone, sotalol, dofetilide, quinidine, procainamide, disopyramide).

 -  QTc greater than 450msec long QT-syndrome (own or with a family history) or with
 a family history of sudden unexplained death.

 -  Left branch bundle block (LBBB), or subjects who have been hospitalized for heart
 failure of cardiac etiology, in the previous 6 months, and subjects who have
 significant and persistent left-ventricular dysfunction (LVEF less than 40%).

 -  History of in the preceding 3 months, significant and persistent arrhythmias such
 as ventricular fibrillation or tachycardia, or atrial fibrillation or flutter.

 -  Symptomatic coronary artery disease.

 -  Presence of severe cardiac disease (New York Heart Association Classification
 greater than or equal to III) and/or abnormal ECG, considered by the investigator
 to be unsafe for the study.

 12. Liver disease or liver injury as indicated by abnormal liver function tests such as
 SGOT (AST), SGPT (ALT), gamma-GGT, alkaline phosphatase, or serum bilirubin. The
 Investigator should be guided by the following criteria:

 -  Any single parameter may not exceed 2 times the upper limit of normal (ULN). A
 single parameter elevated up to and including 2 times the ULN should be
 re-checked once more as soon as possible, and in all cases, at least prior to
 enrollment/randomization, to rule out lab error.

 -  If the total bilirubin concentration is increased above 2 times the ULN, total
 bilirubin should be differentiated into the direct and indirect reacting
 bilirubin. In any case, serum bilirubin should not exceed the value of 1.6 mg/dL
 (27 micromol/L).

 Re-check results must be within normal limits (or returning to within normal limits)
 in order for subject to qualify.

 13. Total WBC count which falls outside the range of 4500-13,000/microL, or platelets less
 than 100,000/microL at screening.

 14. History of severe hypersensitivity to any biological agents (antibody or soluble
 receptor), including serious allergic reaction (hypotension, wheezing, urticaria),
 lupus-like syndrome or demyelinating disease.

 15. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing or longer
 if required by local regulation.

 16. Administration of live vaccines within 6-month prior to dosing.

 17. History of immunodeficiency diseases, including a positive HIV (ELISA and Western
 blot) test result.

 18. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.

 19. Significant illness within the two weeks prior to dosing or any active systemic
 infection or medical condition that may require treatment or therapeutic intervention
 during the study.

 20. Subjects with:

 -  History or presence of impaired renal function as indicated by clinically
 significantly abnormal creatinine greater than 1.3 mg/dL or blood urea nitrogen
 (BUN) greater than 30 mg/dL, or the presence of greater than +1 albumin on the
 urinary dipstick.

 -  Presence of proteinuria, active sediments, casts or WBCs in urine.

 -  Evidence of urinary obstruction or difficulty in voiding at screening.

 -  History of renal trauma, glomerulonephritis, or subject with one kidney.

 21. History of malignancy (other than basal cell carcinoma or adequately treated
 carcinoma-in-situ of the cervix).

 22. Unable or unwilling to undergo multiple venipunctures because of poor tolerability or
 lack of easy access to veins.

 23. Conditions associated with an immune-compromised condition such as recent surgical
 procedure; or history of drug or alcohol abuse within the 12 months prior to dosing.
 Subjects who are unable to discontinue analgesic medications containing opiates and
 opioids, as well as cannabinoids for medical use.

 24. Participation in any clinical investigation within four (4) weeks prior to initial
 dosing or five half-lives of the investigational agent, whichever is longer, and for
 any other limitation of participation based on local regulations.

 NIH EXCLUSION CRITERIA:

 1. Platelet count less than 100,000 mm(3)

 2. Prothrombin Time International Normalized ration (PT INR) greater than 1.3 or Partial
 Thromboplastin Time (PTT) 3 sec than control