Multicenter Clinical Efficacy and Safety Study of Delayed Release 6MP in Crohn's Disease
Information source: Teva GTC
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Crohn's Disease
Intervention: Delayed Release 6 mercaptopurine (Drug); 6 Mercaptopurine (Drug)
Phase: Phase 1/Phase 2
Sponsored by: Teva GTC
Official(s) and/or principal investigator(s):
Yaron Ilan, MD, Principal Investigator, Affiliation: Hadassah Medical Center
Yaron Ilan, MD, Phone: (02) 6777337, Email: email@example.com
The study is designed to evaluate the clinical efficacy and safety of daily treatment for 12
weeks of oral administration of a delayed release, locally delivered 6MP (mercaptopurine)
drug (80 mg), as compared to standard Purinethol (at a dose of 1-1. 5 mg/kg/body weight), in
alleviating the clinical, immunological and mucosal signs and symptoms of moderately active
Official title: MultiCTR Randomized Double-Blind Double-Dummy Study to Evaluate Clinical Efficacy/Safety of DR 6MP for Targeted Ileal Delivery vs Purinethol in Patients w/Moderately Active Crohn's Disease
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Proportion of subjects with clinical response at study end
Secondary outcome: Time to clinical response
Crohn's Disease (CD) therapy is aimed at reducing inflammation via induction of remission
after a flare-up and maintenance of the remission for as long as possible. Therapies
commonly used for inducing remission are steroids and anti-TNF-a. Standard 6MP, on the other
hand, has a slow onset of action and requires several months of administration before its
therapeutic effects become apparent. Therefore, 6MP is typically used as maintenance
therapy, rather than for remission. Furthermore, serious AE's associated wtih 6MP include
leucopenia, hepatoxicity, pancreatitis and bone marrow suppression, requiring lowering of
dose or treatment discontinuation.
The Teva DR-6MP project was designed to evaluate a new oral 6MP formulation that would
address these limitations. The slow action of standard 6MP, precluding its use as a
treatment for induction of remission, would be offset by a faster-disintegrating, more
soluble formulation with an enteric coating for targeted ileal delivery. This new
formulation designed to open at the terminal ileum, the most commonly affected area of CD
bowel involvement, could deliver higher effective local concentrations of drug to the site
most affected by CD, stimulating an effective local immunological response, resulting in a
cascade of widespread immunological activity, evoking an induction of remission. The safety
of standard 6MP would be improved upon by the fact that negligible levels of the DR-6MP
formulation have been observed in the plasma, obviating the toxicities associated with
systemic 6MP. Moreover, since the DR-6MP dose is fixed and not subject to patient weight,
nor potentially, side-effects, the dose adjustments required for up-titration to optimal
dose, or down-titration due to toxicity, could be avoided.
Previous small, pilot proof-of-concept clinical efficacy and pharmacokinetic studies of the
DR-6MP formulation demonstrated the potential for induction of remission, mucosal healing,
systemic immunological improvement and lower systemic side-effects.
The current study is designed to repeat the earlier studies under larger, more rigorous
conditions in a randomized, double-blind fashion at multiple sites to ascertain if the
initial encouraging results could be repeated. Moreover, a higher dose of 6MP (80 mg) will
be tested to ascertain if presumably higher local concentrations at the disease site can
evince a more robust clinical effect.
Minimum age: 18 Years.
Maximum age: 75 Years.
1. Male or (non-pregnant) female, 18-75 years (incl) at screen.
2. Diagnosed w/CD, appropriately documented/supported by endoscopy or radiology.
3. W/ moderately active CD, w/ screen CDAI score 220-450 (inclusive)
4. Screen lab tests:
- HGB >/= 8. 5 g/dL,
- Platelets >/= 100,000/ mm³
- WBC >/= 3500 mm³
- Serum albumin > 2. 5 g/dL
- ALT, AST, ALK Phos, GGTP,. total and direct bilirubin < 2xULN
5. Subjects may be on stable (for at least 2 wks prior screen) 5-ASA, chronic
antibiotics or low-dose oral steroids (prednisolone-up to 15 mg daily; budesonide-up
to 6 mg daily) and remain on the drug at that dose throughout the study
6. Willing and able to provide written ICF.
1. W/ ulcerative colitis or w/ diagnosis of indeterminate colitis.
2. W/ previous bowel resection due to CD resulting in clinically significant Short Bowel
3. W/ fistulizing CD w/ clinic or radiologic evidence of abscess.
4. W/ clinically significant GI obstructive symptoms or x-ray evidence of fibrosed
5. W/ screen stool culture + for enteric pathogens (Salmonella, Shigella, Campylobacter)
or Clostridium difficile toxin assay.
6. W/ hx of persistent intestinal obstruction, bowel perforation, uncontrolled GI
bleed,abdominal abscess,infection or toxic megacolon.
7. W/ hx of GI tract malignancy or IBD-associated malignant intestinal changes.
8. W/ surgery/major procedure in 4 weeks prior to 1st study dose.
9. Receiving elemental diet or parenteral nutrition.
10. W/ current signs/symptoms of clinically significant/unstable med/surg condition that
precludes safe/complete study participation, determined by med history, PE, ECG, lab
tests or imaging. Such conditions may include severe, progressive or uncontrolled
renal, metabolic, hepatic, hematologic, endocrine, pulmonary, cardiovascular,
psychiatric, neurologic, cerebral or autoimmune disease.
11. W/ serious infections, such as hepatitis, pneumonia, pyelonephritis w/in 12 weeks
prior to 1st study dose. Less serious infections such as acute UR tract infections or
uncomplicated UT infection not considered exclusions - at discretion of PI.
12. W/ currently known malignancy/pre-malignant lesions/hx of malignancy w/in past 5
years, excl basal cell carcinoma.
13. W/ hx of coagulopathy.
14. W/ porphyria as it may interfere w/ assessment of CD abdominal pain.
15. W/ hx of previous thiopurine failure resulting in serious AE (ex: severe
pancreatitis, leucopenia, hepatoxicity or bone marrow suppression) so as to preclude
addtl tx w/ 6MP at any dose
16. Taking w/in 6 months prior to 1st study dose (+during study) Active vaccinations
(live attenuated bacterial/viral pathogens)
17. Taking w/in 6 weeks prior to 1st study dose (+ during study):
- Anti-TNFα (infliximab, etanercept, adalimumab)
- Anti-integrin (natalizumab)
- Anti-neoplastics, incl methotrexate, daunorubicin hydrochloride
18. Taking w/in 4 weeks prior to 1st study dose (+ during study):
- Immunosuppressants such as AZA, 6-MP (i. e., other than 6MP drug assigned during
study), cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide.
- Antibiotics or oral/IV corticosteroids (other than oral prednisolone allowed
during study as rescue therapy as per protocol).
- Tx w/ drugs known to induce/inhibit endogenous hepatic drug metabolism such as
barbiturates, phenothiazines, cimetidine, carbamazepine etc.
- Anti-coagulant therapy such as: heparin, warfarin, acenocoumarol.
- Medications that induce blood dyscrasias or w/ potential for immune dysfunction,
bone marrow depression and/or symptoms of CD (diarrhea, abdominal pain).
- Vaccinations involving inactivated forms of pathogens or purified antigenic
proteins (Note: passive immunization involving antibody inoculations permitted
at any time)
19. Tx w/in 2 wks prior to 1st study dose (+ during study) IV or oral steroids
(prednisolone or budesonide) Antibiotics
Note: 2 impt exceptions (a) Subjects oral steroid or antibiotic dependent with active
CD (CDAI 220-450)in spite of these txs, may remain on tx provided on stable (>=2wks
at screen)dose and remain at that dose throughout study (b) Subjects who require
steroid-rescue during study
20. Taking w/in 7 days prior to 1st study dose (+ during study):
- Anticholinergic or other drugs known to affect GI motility.
- Proton pump inhibitors or other drugs affecting gastric acidity
21. W/body weight below 42. 5 kg.
22. Pregnant/nursing at screen, or intend to be during study.
23. Women of childbearing potential not practicing acceptable method of birth control
[acceptable methods: surgical sterilization, IUD, contraceptive (oral, patch, or
long-acting injectable), partner's vasectomy, double-protection method (condom or
diaphragm w/ spermicide) or abstinence].
24. W/ current/hx of drug and/or alcohol abuse.
25. Largely or wholly bed-ridden and w/ little capacity for self-care.
26. W/ known allergy or hypersensitivity to 6-MP or any inactive component of study drug
(ex: lactose intolerant).
27. Participated in other clinical trial using investigational drugs w/in 12 weeks prior
to 1st study dose.
28. W/ planned elective surgery or hospitalization during study (that may interfere w/
29. W/inability to communicate well w/investigators/staff (i. e., language problem, poor
mental development or impaired cerebral function).
30. Unavailable for trial duration, unable to comply w/schedule, likely to be
noncompliant, or felt unsuitable by PI for any other reason.
Locations and Contacts
Yaron Ilan, MD, Phone: (02) 6777337, Email: firstname.lastname@example.org
Barzilai Medical Center, Ashkelon, Israel; Recruiting
Shmuel-Jorge Delgado, MD, Principal Investigator
Soroka Medical Center, Beer Sheva, Israel; Withdrawn
Rambam Medical Center, Haifa, Israel; Recruiting
Yehuda Chowers, MD, Principal Investigator
Bnai Zion Hospital, Haifa, Israel; Recruiting
Alexandra Lavy, MD, Principal Investigator
Hadassah Medical Center, Jerusalem, Israel; Recruiting
Ilan Yaron, MD, Principal Investigator
Shaarei Tzedek Medical Center, Jerusalem, Israel; Recruiting
Eran Goldin, MD, Principal Investigator
Meir Medical Center, Kfar Saba, Israel; Recruiting
Fred Konikoff, MD, Principal Investigator
Holy Family Hospital, Nazareth, Israel; Not yet recruiting
Rifaat Safadi, MD, Principal Investigator
Kaplan Medical Center, Rehovot, Israel; Recruiting
Ehud Melzer, MD, Principal Investigator
Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Recruiting
Sigal Fishman, MD, Principal Investigator
Sheba Medical Center, Tel Hashomer, Israel; Recruiting
Adi Lahat-Zok, MD, Principal Investigator
Assaf Harofeh, Zerifin, Israel; Recruiting
Chaim Shirin, MD, Principal Investigator
Previous pilot studies (proof of concept efficacy and pk studies) conducted on the DR6MP tablet
Starting date: November 2010
Last updated: August 14, 2011