HF2 Therapy in the Treatment of Active Ulcerative Colitis

1.1 Objective: To investigate the efficacy and safety of HF2 to induce remission in patients with active UC.

1.2 Methods:

This will be a two-stage study:

Stage 1 will comprise an open label single arm exploratory study of 10 active UC patients investigating HF2 therapy for induction of remission in outpatients with active UC.

Stage 2: If clinical response is achieved in ≥ 3 patients and no significant safety signals will emerge, the investigators will proceed to a prospective pilot randomized placebo-controlled study.

Stage 1: Open label study

1.7 Primary outcome stage I The primary outcome will be the percentage of patients in clinical remission (SCCAI score of ≤2) at week 4 after initiation of therapy

Secondary outcomes (phase 1):

1.7.1 The percentage of patients who had a rapid clinical response at day 7 after induction of therapy 1.7.2 The percentage of patients who had a clinical response at week 4 after initiation of therapy 1.7.3 Improvement in endoscopic score at week 4 compared to baseline according to modified endoscopic Mayo score (improvement of ≥ 1 point) 1.7.4 Achievement of mucosal healing (endoscopic modified Mayo score of ≤1). 1.7.5 Percentage of patients who achieve normalization and/or >50% improvement in C-reactive protein (CRP) and/or calprotectin levels (computed out of patients with abnormal values at baseline for these indices).

1.7.6 Time-to-response defined as number of days to achieve a drop of ≥3 points of the SCCAI score.

1.7.7. Time-to-ceasing of bleeding, defined as number of days for complete absence of blood in stools (SCCAI bleeding sub-score of 0), in those patients who has at least some blood in stool at entry (SCCAI bleeding sub-score of 1 or more).

1.7.8 The percentage of patients in clinical remission at day 7 after induction of therapy.

1.7.9. Improvement in IBD quality of life as gauged by questionnaire (IBDQ). 2 Intervention: Patients diagnosed with active UC will receive HF2 therapy for 4 weeks. 3 Procedures: 3.2 At inclusion: clinical and endoscopic assessment, blood and stool tests, cardiac echo and liver ultrasonography 3.4 clinical and endoscopic assessment, blood and stool tests, cardiac echo and liver ultrasonography

Stage II: A multicenter randomized placebo controlled trial. The study will be performed in Sheba Medical Center and up to 2 additional European centers (TBD). For this stage of the trial , the patients will received HF2 combintation or similar (as described above) (2:1 allocation) for 8 weeks. After completion of 8 weeks, all responders previously on active drug will receive additional 8 weeks of oral curcumin or placebo as per original arm.

Primary outcome: a composite outcome of clinical response (reduction in SCCAI of ≤3 OR achievement of clinical remiision defined as SCCAI ≤2) coupled with an objective evidence of response ( Mayo score improvement of ≥1 or 50% FcAL reduction ) at week 8

Secondary outcomes:

• Percentage of patients in clinical remission (SCCAI≤2) at week 8
• The percentage of patients who had a clinical response at week 8 after initiation of therapy
• Improvement in endoscopic score at week 8 compared to baseline according to endoscopic Mayo score (improvement of ≥ 1 point)
• Achievement of mucosal healing (endoscopic modified Mayo score of ≤1) at week 8
• Percentage of patients who achieve normalization and/or >50% improvement of CRP and/or calprotectin levels (computed out of patients with abnormal values at baseline for these indices) at week 8.
• Percentage of patients in corticosteroid-free clinical remission at week 8
• Improvement in IBD quality of life as gauged by questionnaire (IBDQ).
• Percentage of patients in clinical remission at week 16
• Percentage of patients with clinical response at week 16
• Percentage of patients with normalized fecal calprotectin and CRP

6.2. Intervention: Patients will be randomized into one of two arms: HF2 or placebo formulation (2:1 proportion) for 8 weeks. Following the first 8 weeks, responders w ill receive an additional 8 weeks of curcumin 1.5 g/d or placebo (as per original arm).

Patients will undergo clinical, laboratory (CRP, biomarkers, blood chemistry, CBC_biomarker (CRP and fecal calprotectin, at week 0,4,8 and 16 , and endoscopic assessment at baseline and week 8. Cardiac echo and liver US will be performed at week 0 and 8.

Corticosteroid tapering will be allowed as per treating physician's discretion after week 8.

Inclusion criteria

• Established diagnosis of UC
• Age- 18-70
• active UC defined by a Simple Clinical Colitis Activity Index (SCCAI) score ≥5 and a score of ≥2 in the modified Mayo endoscopic sub-score.
• Stable medication dose or if the patient has discontinued previous treatment :

for Infliximab or Vedolizumab - at least one month after patient received last dose; for Adalimumab, Golimumab, immunomodulator, corticosteroids, 5ASA - at least two weeks after patient received last dose.

Exclusion criteria

• non-controlled renal or liver disease, hypertension, cardiovascular disease, cerebrovascular disease, chronic pancreatitis, diabetes mellitus, gallstone disease, uncontrolled migraines or neurological disorders
• significant laboratory abnormalities, including anemia with hemoglobin <10, leucopenia , thrombocytopenia , abnormal coagulation tests , or elevation of liver or kidney function tests above the normal values.
• active infection, sepsis or pneumonia.
• pregnancy/nursing
• known allergy to the compound