HF2 Therapy in the Treatment of Active Ulcerative Colitis
Condition: Ulcerative Colitis
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This is a phase I-II study with the herbal formulation (HF2) for treatment of active
      ulcerative colitis

      This will be a two-stage study:

      Stage 1 will comprise an open label single arm exploratory study of 10 active ulcerative
      colitis (UC) patients investigating oral HF2 therapy for induction of remission in
      outpatients with active UC. Active disease is defined as (SCCAI) score ≥5 and a score of ≥2
      in the modified Mayo endoscopic sub-score. Clinical remission is defined as a SCCAI score of
      ≤2 The patients will receive HF2 therapy for 4 weeks. Stage 2: If clinical response (defined
      as a drop of ≥3 points of the SCCAI score ) is achieved in ≥ 3 patients and no significant
      safety signals will emerge, the investigators will proceed to a prospective pilot randomized
      placebo-controlled study. Patients will be randomized into one of two arms: HF2 once daily or
      placebo formulation (2:1 proportion) for 8 weeks.

      The primary outcome for stage 2 is a co-primary outcome of clinical response (reduction in
      SCCAI of ≤3 OR achievement of clinical remission defined as SCCAI ≤2) coupled with an
      objective evidence of response (Mayo score improvement of ≥1 or 50% FcAL reduction) at week
      8.

      Patients clinically responding at week 8, will be eligible to continue in an 8-weeks
      extension study to receive either placebo or 1.5gr/day curcumin alone until week 16, as per
      their original allocation. Exploratory analysis of outcomes for the extension study will
      include the percentage of patients in clinical remission (SCCAI≤2) and the percentage of
      patients who maintained clinical response (reduction in SCCAI of ≥3 point compared to week
      0).
    

Detailed description: 
      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.
    

Intervention name(s): HF2
Intervention type(s): Dietary Supplement
Intervention description(s): placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: After an initial open-label run-in (if successful) the patients will be randomized to receive HF2 or placebo (2:1 allocation)
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment