A Phase II/III, Randomised, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Oral Controlled-Ileocolonic-Release Nicotinamide (CICR-NAM) for Induction and Maintenance Therapy in Patients With Mild to Moderately Active Ulcerative Colitis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 459
- 试验地点
- 27
- 主要终点
- Symptomatic remission
研究概览
简要总结
Double-blind, randomised, placebo-controlled phase II / III trial evaluating efficacy and safety of two different doses (2 g/d or 3 g/d) of oral controlled-ileocolonic-release nicotinamide (CICR-NAM) compared to placebo in patients with ulcerative colitis (UC).
The intended therapeutic use of CICR-NAM is to improve intestinal inflammation in adults with UC by topically increasing nicotinamide supply in the ileocolonic region and thus favourably influencing the composition of intestinal microbiota
详细描述
ORNATUS 1 is a double-blind randomised trial evaluating the efficacy and safety of CICR-NAM in patients with mild to moderately active UC. The trial includes a 12-week induction period and a 40-week maintenance period. Patients will be randomised 1:1:1 placebo vs. 2 g/d CICR-NAM vs. 3 g/d CICR-NAM prior to induction treatment and will remain in the allocated dose level in the maintenance period, which results in a 52-week treatment in a treat-through design. An optional open label arm with 3 g/d CICR-NAM will be implemented for patients that have completed the induction period and show worsening of disease activity at the end of the induction period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female patients with UC and 18 to 80 years of age (at the time of signing the informed consent).
- •Ability to understand and comply with the protocol.
- •Signed written informed consent.
- •Disease-specific:
- •Documented diagnosis of UC, with a minimum disease duration of 3 months prior to screening and ≥ 1 relapse, clinically defined using established criteria within the last 12 months.
- •Histology supportive for the diagnosis of UC.
- •Mild to moderate disease activity (at screening): modified Mayo score (mMS) 4-7 RB ≥ 1, endoscopic score ES ≥1 and SF ≥
- •RHI > 4 (at screening endoscopy).
- •Disease extent >15 cm from the anal verge (at screening endoscopy).
- •Elevated level(s) of C-reactive protein (CRP) and/or faecal calprotectin during the screening period (levels above the reference range, measured by local laboratories).
- •Full colonoscopy with no signs of malignancy either during screening or within one year before screening.
- •Medication:
- •In the case of no oral 5-ASA therapy within the last 2 weeks before entry into screening with informed consent, any prior oral 5-ASA therapy is permitted and the patient is not allowed to receive 5-ASA during the study. In the case of oral 5-ASA therapy within 2 weeks before entry into screening with informed consent, the 5-ASA therapy should have been ongoing for > 3 months, should not be increased ≥ 4 weeks before screening endoscopy and should remain stable for ≥ 1 week before screening endoscopy at the maximum dose according to label or lower. This 5-ASA baseline medication must be kept stable in the induction period and may be reduced (but not increased again) in the maintenance period. In cases in which 5-ASA is dosed higher than the approved dose, the dose will be adjusted to the maximum approved dose at the time of randomization.
排除标准
- •General health and UC:
- •Diagnosis of CD, microscopic colitis, ischaemic colitis, radiation colitis or indeterminate colitis.
- •Infectious colitis, diverticulitis or segmental colitis associated with diverticulosis (SCAD) within the last 6 months before screening.
- •Current or past diagnosis of complex fistulae, intra-abdominal or peritoneal abscesses, strictures with obstructive symptoms.
- •Severe UC disease activity (modified Mayo score >7).
- •Severe extraintestinal manifestations of UC requiring special treatment.
- •Steroid-dependent or steroid-refractory UC.
- •Foreseeable need for hospitalisation.
- •Previous colonic surgery, except for appendectomy.
- •Stools positive for enteric pathogens; Clostridium difficile toxin (CDT)-positive infection; indications for other relevant infections including cytomegalovirus colitis, each at screening.
- •Current or history of colon carcinoma, high grade colonic dysplasia or other malignancies except for completely resected basal cell carcinoma and squamous cell carcinoma of the skin.
- •Moderate to severe anaemia (haemoglobin <9 g/dL) at screening.
- •Moderate to severe renal impairment (glomerular filtration rate <60) at screening.
- •Relevant bleeding or thrombotic disorders.
- •Alcohol or drug abuse within the last 2 years.
- •Medications:
- •Rectal topical 5-ASA and/or rectal budesonide therapy (enemas, foams or suppositories) ≤ 2 weeks prior to screening endoscopy (up to 3 single doses allowed).
- •Use of oral corticosteroids and/or oral budesonide ≤ 4 weeks prior to screening endoscopy.
- •Previous use of immunosuppressants, Janus kinase inhibitors, sphingoside-1-phosphate receptor modulators or biologics.
- •Use of antibiotics for the treatment of UC or probiotic medication within 6 weeks prior to screening endoscopy.
- •Any need of parenteral therapies for the therapy of UC (except iron infusions).
- •Known hypersensitivity towards any component of the CICR-NAM or placebo tablets.
- •Regulatory requirements
- •Participation in a clinical trial within 4 weeks prior to screening for this trial or intake of an investigational medicinal product (IMP) within the last 8 weeks or 5 half-lives (whichever is longer) prior to screening (or longer if necessary in the investigator's discretion).
- •Patients under legal supervision or guardianship, including patients, who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
- •Patients who are dependent on the investigator or the sponsor.
- •Pregnant or breastfeeding women.
- •Women of childbearing potential (WoCBP) not using highly effective contraception till at least 1 month after last dosing of IMP.
- •Male participants with female partners of childbearing potential who are not willing to use a highly effective contraception till at least 1 month after last dosing of IMP.
- •Indications that the patient may be unable to comply with the trial procedures, e.g. language barriers precluding adequate understanding or cooperation.
- •Any circumstances or medical conditions which could contradict a trial participation and lead the investigator to assess the patient as unsuitable for trial participation for any other reason.
研究组 & 干预措施
High-Dose (3 g/d CICR-NAM (blinded))
To maintain blinding for patients and investigators in the induction and maintenance treatment, all patients self-administer 6 tablets per day. In the high-dose arm, subjects receive 6 tablets of verum CICR-NAM and 0 tablets of placebo CICR-NAM per day, resulting in a total daily intake of 3 g/d CICR-NAM
干预措施: High-Dose CICR-NAM (Drug)
Low-Dose (2 g/d CICR-NAM (blinded))
To maintain blinding for patients and investigators in the induction and maintenance treatment, all patients self-administer 6 tablets per day. In the low-dose arm, subjects receive 4 tablets of verum CICR-NAM and 2 tablets of placebo CICR-NAM per day, resulting in a total daily intake of 2 g/d CICR-NAM
干预措施: Low-Dose CICR-NAM (Drug)
Placebo (0 g/d CICR-NAM (blinded))
To maintain blinding for patients and investigators in the induction and maintenance treatment, all patients self-administer 6 tablets per day. For the placebo arm, subjects receive 0 tablets of verum CICR-NAM and 6 tablets of placebo CICR-NAM per day, resulting in a total daily intake of 0 g/d CICR-NAM
干预措施: 0 g/d CICR-NAM (blinded) (Drug)
Open-Label (3 g/d CICR-NAM (blinded))
Patients that have completed the induction period and show worsening of disease activity at the end of the induction period will be allowed to switch to the open-label arm to receive 6 tablets of verum CICR-NAM of 0 tablets of placebo CICR-NAM per day, resulting in a total daily intake of 3 g/d CICR-NAM
干预措施: Open-Label (Drug)
结局指标
主要结局
Symptomatic remission
时间窗: Baseline - Week 12
The proportion of subjects that show symptomatic remission. Symptomatic remission is achieved if: Mayo SF = 0 or 1 (and SF no greater than baseline) and Mayo RB = 0 as well as a reduction from Mayo ES = 2 or 3 at baseline by at least one point or a reduction from Mayo ES = 1 at baseline to Mayo ES = 0 or, in case of a constant Mayo ES = 1 from baseline, an objective second marker of improvement (histologic improvement to RHI ≤ 4)
Clinical remission
时间窗: Baseline - Week 52
The proportion of subjects that show clincial remission. Clinical remission is achieved if: Mayo SF = 0 (or SF = 1 with a ≥ 1-point decrease from baseline), Mayo RB = 0, and Mayo ES ≤ 1 (excluding friability) (for constant Mayo ES = 1 from baseline, histologic improvement to RHI ≤ 4)
次要结局
未报告次要终点