Efficacy, Pharmacokinetics, Tolerability, Safety of SB012 Intrarectally Applied in Active Ulcerative Colitis Patients

NCT02129439 | Completed Phase 1 DMC

• 1 other identifier: SB012/01/2013
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 3

Brief Summary

Ulcerative colitis (UC) represents one of the major entities of idiopathic inflammatory bowel diseases which are defined as chronically relapsing inflammations of the gastrointestinal tract not due to specific pathogens. It is characterised by a superficial, continuous mucosal inflammation, which predominantly affects the large intestine. The clinical course is typically marked by periods of asymptomatic remission punctuated by unpredictable recurrent attacks. The symptoms of the patients are marked by persistent diarrhoea with severe faecal urgency and often incontinence, rectal bleeding, abdominal cramping and weight loss. Uncontrolled activation of mucosal effector T cells has been identified as the main pathogenic mechanism involved in the initiation and perpetuation of intestinal inflammatory reactions. Patients with moderate UC are initially treated with mesalazine, applied both orally and rectally. If symptoms do not improve, systemic corticosteroids are to be administered. Patients who do not respond to systemic corticosteroids may become eligible for treatment with a calcineurin inhibitor or an anti-tumor necrosis factor (TNF)α antibody. Alternatively, patients may have to undergo major colorectal surgery. Patients who do not adequately respond to these treatment strategies exhibit serious drawbacks. Colorectal surgery may result in a severely compromised quality of life. Therefore, patients with moderate or severe UC may significantly benefit from new therapeutic alternatives. The transcription factor GATA-3 is an interesting target for a novel therapeutic strategy in UC. GATA-3 is the key regulation factor of Th2-driven immune responses. It is indispensable for the differentiation and activation of Th2 cells, integrates Th2 signals, and induces Th2 cytokine expression. Results of a recent clinical trial in children showed that GATA-3 is involved in the pathogenesis of the acute phase of UC. The investigational product SB012 contains the DNAzyme hgd40 that targets GATA-3. By cleaving GATA-3 mRNA hgd40 reduces specific cytokine production and thereby reduces key features of mucosal inflammation. DNAzymes are completely generated by chemical synthesis, not by use of any living organism and are therefore not biological drugs. This study will evaluate the efficacy, safety, tolerability and pharmacokinetics of the topical formulation SB012 available in a concentration of 7.5mg/ml hgd40 in 30ml PBS once daily as a ready-for-use enema in patients with active UC.

Conditions

Colitis, Ulcerative

Keywords

Antisense oligonucleotide; Colitis Ulcerosa; Ulcerative colitis; Phase II; Transcription factor GATA-3; intrarectal application; proof-of-concept

Outcome Measures

Primary Outcomes (1)

• Efficacy: Total Mayo score (4 weeks comparison)

  Change in Total Mayo score after 4 weeks of treatment compared to baseline value in the active treatment group (SB012) versus placebo. The Total Mayo score is a 13-point ordinal scale for the assessment of concurrent severity of ulcerative colitis. It comprises four components: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment of disease severity. Each component has four grades ranging from 0 to 3. The Total Mayo score ranges from 0 to 12, with 12 representing the most severe disease.

  Baseline (Visit 2) to day 28 (Visit 7) (28 days)

Secondary Outcomes (4)

• Efficacy: Total Mayo score (8 weeks comparison)

  Baseline (Visit 2) to End-of-Study Visit10 (56 days)

• Efficacy: Endoscopic Mayo score (4 and 8 weeks comparison)

  Baseline (Visit 2) to Visit 7 and Visit 10 (28 and 56 days)

• Efficacy/Pharmacodynamics: Glucocorticoid consumption

  Baseline (Visit 2) to day 56 End of Study Visit 10 (56 days)

• Safety: Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE)

  Visit 1 (Screening) to Visit 10 (End of Study - 56 days) or Visit X (Early Study Termination)

Other Outcomes (4)

• Pharmacokinetic (PK) analysis

  First treatment Day 1/day 2 (Visit 3/4) to Last treatment day 28/29 (Visit 7/8)

• Exploratory analysis: Systemic biomarker plasma levels

  Day 1 (Visit 3) to Day 28 or Day 56 (V7 or V10)

• Exploratory analysis: Systemic biomarker plasma levels

  Day 1 (Visit 3) to Day 28 or Day 56 (V7 or V10)

Study Arms (2)

SB012

EXPERIMENTAL

SB012 will be available in this clinical trial in a concentration of 7.5 mg/ml hgd40 in 30ml PBS. The maximum daily dose will not exceed 225mg. The study will be continued until 18 subjects have completed the four-week treatment phase according to te protocol. 12 of the 18 subjects will receive verum SB012 (in a 2:1 randomization SB012:Placebo)

Drug: SB012

Placebo

PLACEBO COMPARATOR

Placebo will be administered with an identical volume of 30ml PBS. The study will be continued until 18 subjects have completed the four-week treatment phase according to te protocol. 6 of the 18 subjects will receive placebo (in a 2:1 randomization SB012:Placebo)

Drug: Placebo

Interventions

SB012 DRUG

The treatment phase lasts 28 consecutive days. The IMP will be administered for the first time at the study site in the morning on Day 1 (IMP administration training by study site staff). The final administration will be performed at the study site in the morning of Day 28. On all other treatment days (Day 2 to Day 27), the IMP will be self-administered by the subject at home. SB012 will be available in this clinical trial in a concentration of 7.5mg/ml hgd40 in 30ml PBS (Maximum daily dose: 225mg) The IMP is formulated as an enema and will be administered in this clinical trial by the rectal route. The enema is a ready-for-use preparation. No further preparation steps are required. No modifications are permitted to the dosing regimen except for premature study discontinuation.

Also known as: Active drug substance is hgd40

SB012

Placebo DRUG

Intervention of placebo-treated subjects does not vary to SB012-treated subjects. The treatment phase lasts 28 consecutive days. Placebo will be administered for the first time at the study site in the morning on Day 1 (Administration training by study site staff). The final administration will be performed at the study site in the morning of Day 28. On all other treatment days (Day 2 to Day 27), the IMP/Placebo will be self-administered by the subject at home. Placebo will be administered with a volume of 30ml. The IMP/Placebo is formulated as an enema (plastic rectal tube) and will be administered in this clinical trial by the rectal route. The enema is a ready-for-use preparation. No further preparation steps are required.

Also known as: Active ingredient-free PBS solution

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The trial population consists of adult subjects of both sexes with active ulcerative colitis aged 18 to 75 years.
• Fully capable to give informed consent.
• Mentally able to understand the nature, significance, implications and risks of the clinical trial and to follow instructions of the trial staff.
• Written informed consent
• Clinical Mayo Score of ≥3
• Total Mayo Score of ≥6
• Endoscopic Mayo score ≥2 in the sigmoid
• Body mass index ≥18.0 to ≤29.0kg/m2 and body weight ≥50 to ≤100kg
• Negative urine pregnancy test (female subject only)
• Using two methods of contraception

You may not qualify if:

• Colectomy and presence of ileal pouch-anal anastomosis or ileorectal anastomosis
• Diagnosis of ulcerative proctitis, fulminant colitis, toxic megacolon, of colitis indeterminata or Crohn's disease
• Ileostoma
• Anti-TNFα treatment with adalimumab, certolizumab, etanercept, golimumab, or infliximab ≤4 weeks prior to screening visit.
• Change in systemic glucocorticoid treatment ≤1 weeks prior to screening visit
• Change in 5-Aminosalicylic Acid (ASA) therapy ≤1 week prior to screening visit
• Start of treatment with an immunosuppressive agent ≤3 months prior to screening visit
• Change in treatment with an immunosuppressive agent ≤4 weeks prior to baseline visit
• Planned concomitant therapeutic administration of suppositories or foams or enema other than the IMP.
• Impaired blood coagulation (Quick value \<50% and/or partial thromboplastin time (PTT) \>55sec and/or platelet count \<50.000/μl.)
• Signs of renal insufficiency
• Signs of hepatic insufficiency.
• Current treatment with drugs of high hepatotoxic potential.
• Evidence of recent alcohol abuse.
• Acute or chronic heart failure with NYHA functional class III or IV.

Sponsors & Collaborators

• Sterna Biologicals GmbH & Co. KG: lead

Study Sites (3)

Braunschweig Municipal Hospital - Medical Clinic 1

Braunschweig, 38126, Germany

Location

Department of Medicine 1 - Gastroenterology, Pneumology and Endocrinology, University Clinic Erlangen, Germany

Erlangen, 91054, Germany

Location

Asklepios West Hospital Hamburg - Division Gastroenterology

Hamburg, 22559, Germany

Location

MeSH Terms

Conditions

Colitis, Ulcerative

Condition Hierarchy (Ancestors)

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Inflammatory Bowel Diseases; Colonic Diseases; Intestinal Diseases

Study Officials

• Markus F. Neurath, Prof. Dr.

  Department of Medicine 1 - Gastroenterology, Pneumology and Endocrinology, University Clinic Erlangen, Germany

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2014
• First Posted: May 2, 2014
• Study Start: April 1, 2014
• Primary Completion: June 22, 2017
• Study Completion: June 22, 2017
• Last Updated: March 9, 2018

Record last verified: 2017-07

Locations

DE (3)