1. Curcumin Add-on Therapy for Induction of Remission in Mild-to-Moderate Ulcerative Colitis: Results of a Multi-Center, Prospective, Randomized, Placebo-Controlled, Double-Blind Study
Alon Lang1*, Nir Salomon1,2*, Uri Kopylov1 , Adi Lahat 1, Ofir Har-Noy1, Jessica Ching3 , Pui Kuan Cheong3 , Justin Wu 3 ,Benjamin Avidan1, Dorit Gamus2, John Kaimakliotis4, Rami Eliakim1, Siew Ng.3*, Shomron Ben-Horin1*
Gastroenterology Department1 & Complementary Medicine Service2, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Israel, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong3 , Central IBD clinic, Nicosia, Cyprus4.

2. Introduction Incidence of IBD is increasing over last decades
Growing challenge to answer unmet medical need
New therapeutic agents, Combination therapies.
Vind A, Am J Gastroenterol 2006
Ng SC, Gastroenterology 2013

3. Curcumin A New Direction?
Curcumin is an active phyto-chemical compound derived from Rhizoma Curcuma Longa.
Researched areas:
Neurodegenerative diseases
Athritis
Cancer
Inflammatory diseases

4. Mechanism in animal models of IBD
Suppresses NF-B
Activity in Colonic Mucosa
Alters Expression of Cytokine
Genes
Reduces CD4 T cells infiltration into lamina propria
Sugimoto K. GASTROENTEROLOGY 2002;123:1912–1922
Uno K., GASTROENTEROLOGY 2006;131:497–509

5. Effects in Animal Models of IBD
Attenuated experimental TNBS-induced colitis
Attenuates macroscopic damage in murine colitis
Improves mortality rate of mice with TNBS-induced colitis
Uno K., GASTROENTEROLOGY 2006;131:497–509
Am J Physiol Gastrointest Liver Physiol 285: G235–G243, 2003.

6. Clinical Trials in Humans
Outcome
Design
Patients
Year
Author Journal
Clinical improvement
Open-label 10
2005
Holt et al
Digestive diseases and sciences
Superior to placebo for maintenance of remission
Randomized, Placebo-Controlled 82
2006
Hanai et al
Clinical Gastroenterology and Hepatology
Superior to placebo for remission induction (PP)
(topical enema) 45
2014
Singla et al
Journal Crohn’s and Colitis
Holt PR, Dig Dis Sci Nov;50(11):
Hanai Y., Clin Gastroenterol Hepatol Dec;4(12):1502-6
Singla V., J Crohns Colitis Mar;8(3):

7. Preliminary in-vitro experiments: CD4 Proliferation
Inhibition of CD4 T cell Proliferation by Curcumin
Medium
83.72% Proliferation
Curcumin 2.5uM
63.54% Proliferation
Curcumin 10uM
44.98% Proliferation

8. Preliminary in-vitro experiments: Cytokine Suppression
Inhibition of Monocyte secretion of TNF-alpha & IL-8 by Curcumin

9. Curcumin, but not mesalamine, inhibits activated T-cells: Implications for combo curcumin-mesalamine therapy
T3 + 5ASA 0.5mM
T3 + 5ASA 2mM
T3 + Curcumin 2.5uM+5asa0.5mM
T3 + Curcumin 2.5uM+5asa 2mM
Salomon, N. Gastroenterology & Hepatology, 2012.

10. Mild-Moderate UC
Most UC patients exhibit a mild-moderate disease activity
Up to 50% of patients do not fully respond to 5ASA treatment
Odes et al, Alimentary Pharmacology and Therapeutics

11. ~10% 20-30% 60-70% Corticosteroids Purine analogues Anti-TNFs
Third Line
Unresponsive
Disease
Second Line Treatment
Moderate-Severe Disease
Corticosteroids
Purine analogues
Anti-TNFs
First Line Treatment
Mild-Moderate Disease/Remission
5 Amino-salicylic acid (5ASA)
Oral/Topical
~10%
20-30%
60-70%

12. Moderate-Severe Disease 5 Amino-salicylic acid (5ASA)
Third Line
Unresponsive
Disease
Second Line Treatment
Moderate-Severe Disease
Corticosteroids
Purine analogues
Anti-TNFs
5 Amino-salicylic acid (5ASA)
Oral/Topical ? ?
UNMET NEED
~50%
Unresponsive Mild-Moderate Disease

13. Points to Investigate
Could curcumin be used to induce remission in mild-moderate active UC patients failing optimized first-line (5ASA) treatment?
Could curcumin add-on therapy spare escalation to steroid and/or immune-suppressing treatment?

14. Optimization of topical 5ASA treatment
Procedures
Screening
Baseline
Conclusion
Age 18-70
Mild-Moderate disease (SCCAI score 12 ≥ 5)
> 4w optimized oral 5ASA dosage
No recent steroids or anti-TNFs use
Mild-Moderate disease (SCCAI score 12 ≥ 5)
Sigmoidoscopy showing active disease
Neg C.diff culture
CBC, CRP, LFT
SCCAI
Sigmoidoscopy
CBC, CRP, LFT
Run-in (2 weeks)
Optimization of topical 5ASA treatment
Treatment (4 weeks)
Curcumin / Placebo

15. Outcomes Primary outcome: Secondary outcomes:
The percentage of patients in clinical remission
(SCCAI ≤2 + ≥3 points drop in SCCAI)
Higgins P. et al , Gut.
Secondary outcomes:
Clinical improvement (≥3 points drop in SCCAI)
Endoscopic improvement (>1 point drop in partial Mayo score)
Improvement in quality of life (IBDQ questionnaire)

16. Statistical analysis
Continuous variables analysed by Student t-test or Mann-Whithney test, and categorical parameters by Fisher exact test, according to intention to treat (ITT) and per-protocol treatment (PPT)
Power calculation was not performed for this pilot exploratory trial because the effect size of add-on curcumin was unknown at the time the trial was conceived
Recruitment goal was set at 50 patients

17. Baseline Characteristics
Curcumin (n=26)
Placebo
(n=24)
P value
Mean age±SD
40.4±12.7
41.4±13.9 NS
Sex(m/F)
17/9
16/8
Smoking
15% 8%
Duration of Disease±SD (years)
7.1±6
5.0±4.1
Proctitis
38%
25%
Left-sided
40%
62%
Extensive
16%
13%
5ASA
85%
80%
5ASA+IM
20%
Mean SCCAI±SD
6.5±1.5
7.0±1.8
Mean Partial Mayo score±SD
1.9±0.4
2.1±0.39
Median duration of topical 5ASA use, years (IQR) *
1 (1-3)
1 (1-1.75)
Median duration of oral 5ASA use, years (IQR) *
2 (2-4)
2 (2-3)

18. Trial Flow Chart 97 Patients screened 47 patients excluded:
31 not meeting inclusion criteria
7 entered remission after topical 5ASA optimization
5 had normal sigmoidoscopy showing inactive disease
4 tested positive for C.diff
50 patients randomized
26 patients allocated to receive curcumin
24 patients allocated to and received placebo
1 patient was hospitalized before initiation of drug
1 lost to follow-up
1 withdrew consent
26 patients included in ITT analysis
25 patients included in PP analysis
24 patients included in ITT analysis
22 patients included in PP analysis

19. Results: Clinical Response and Remission

20. Results: Endoscopic Response and Remission

21. Results: Endoscopic Response and Remission
Endoscopic image showing marked erythema, loss of vascular pattern, tissue friability

22. Results: Endoscopic Response and Remission
Same patient after 4 weeks of curcumin add-on therapy Image showing inactive disease with nearly complete mucosal healing.

23. UNMET NEED Corticosteroids Purine analogues Anti-TNFs
Third Line
Unresponsive
Disease
Second Line Treatment
Moderate-Severe Disease
Corticosteroids
Purine analogues
Anti-TNFs
First Line Treatment
Mild-Moderate Disease/Remission
5 Amino-salicylic acid (5ASA)
Oral/Topical
UNMET NEED

24. “Optimized” First Line Treatment
Third Line
Unresponsive
Disease
Second Line Treatment
Moderate-Severe Disease
First Line Treatment
Mild-Moderate Disease/ Disease Remission
Curcumin Add-on Therapy +
5ASA compounds (oral/topical) and/or immuno-modulators
“Optimized” First Line Treatment
5ASA compounds (oral/topical)
Curcumin Add-on Therapy

25. Limitations Small sample size Lack of follow-up
No prior dose-finding study
Low placebo response

26. Summary
Curcumin may be a safe and promising agent in the treatment of IBD (no adverse events recorded)
Curcumin-5ASA combo therapy presents a new integrative strategy for mild-moderate UC
More large well-designed clinical trials are warranted
Lang A et al, Clin Gastroentrol Hepatol (in press)

27. Acknowledgements Sheba Medical Center:
Dr. Alon Lang
Dr. Shomron Ben-Horin
Dr. Ella Fudim
Prof. Rami Elyakim
Chinese University of Hong Kong:
Dr. Siew NG
Prof. Justin Wu
Jessica Ching
Nicosia IBD Center
Dr. John Kaimakliotis

28. Thank you
Nir Salomon (C.Ac, C.Hb), Integrative Medicine Clinic, Gastroenterology Department, Sheba Medical Center.

29. Curcumin in the Treatment of IBD: Basic and Clinical Research
Nir Salomon
(C.Ac, C.Hb)
Integrative Medicine Unit
Gastroenterology Department
Sheba Medical Center

30. Where are we going? 1 2 3 “Assessing the toolbox”
Screening for potential therapeutic agents 2
“Find the role”
Establish a well-defined approach 3
“Put to the test”
Well-designed, randomized, controlled trials

31. ~10% 20-30% 60-70% Corticosteroids Purine analogues Anti-TNFs
Third Line
Unresponsive
Disease
Second Line Treatment
Moderate-Severe Disease
Corticosteroids
Purine analogues
Anti-TNFs
First Line Treatment
Mild-Moderate Disease/Remission
5 Amino-salicylic acid (5ASA)
Oral/Topical
~10%
20-30%
60-70%

32. Mean values of Endoscopic Score

33. Points to Investigate
Could curcumin be used to induce remission in mild-moderate active UC patients failing optimized first-line (5ASA) treatment?
Perhaps. Larger trials using curcumin adjunct therapy warranted.
Could curcumin add-on therapy spare escalation to steroid and/or immune-suppressing treatment?
Perhaps. Longer well-designed trials warranted.