Efficacy and Tolerability of ZED1227 in Patients with Celiac Disease Experiencing Symptoms Despite a Gluten-Free Diet: A Randomized, Double-Blind, Placebo-Controlled Phase II Trial
- Trial ID
- 2023-506150-21-00
- Protocol
- CEC-013/CEL
- Sponsor
- Dr. Falk Pharma GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II, double-blind, randomized, placebo-controlled trial is to evaluate the efficacy of ZED1227 capsules in improving **celiac disease** symptoms in subjects who continue to experience symptoms and have mucosal damage despite adhering to a gluten-free diet. This is assessed using the Celiac Disease Symptom Diary (CDSD), which is clinically relevant as it addresses the persistent symptoms that affect the quality of life in celiac disease patients.
Secondary objectives include assessing the efficacy of ZED1227 capsules in:
- Changes in duodenal mucosal morphology as measured by morphometry (villous height to crypt depth, VH:CrD).
- Changes in the severity of non-stool gastrointestinal symptoms (abdominal pain, bloating, nausea) as assessed by CDSD.
Participants
The clinical trial involves a total of **63 participants** diagnosed with **Celiac Disease**. The study population includes both male and female subjects, aged between **18 and 80 years**. Participants were selected based on their documented initial biopsy-proven diagnosis of celiac disease or elevated TG2-IgA levels, adherence to a gluten-free diet for at least 12 months, and the presence of moderate to severe gastrointestinal symptoms. The trial population is required to maintain their current gluten-free diet throughout the study. Participants must have a BMI between **17.0 and 35 kg/m²** and a negative diagnosis of **Helicobacter pylori** infection. The selection criteria ensure that the study includes individuals who are experiencing symptoms and have mucosal damage despite following a gluten-free diet. The trial does not exclude vulnerable populations, and both genders are represented. The sponsor has not provided additional information regarding specific lifestyle considerations beyond dietary adherence.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and tolerability of ZED1227 in subjects with **celiac disease** who continue to experience symptoms despite adhering to a gluten-free diet. The trial will involve the administration of ZED1227 in the form of hard capsules, with a placebo group for comparison. The primary objective is to assess the improvement of celiac disease symptoms using the Celiac Disease Symptom Diary (CDSD). The trial is expected to commence on April 30, 2024, and conclude by April 30, 2025, with a total duration of 15 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of celiac disease, and adherence to a gluten-free diet. Baseline visits will follow, where initial assessments and measurements will be conducted. Throughout the trial, participants will attend follow-up visits to monitor changes in symptoms and any adverse effects. The end-of-study visit will mark the completion of the trial, where final evaluations will be performed to assess the primary and secondary endpoints, including changes in gastrointestinal symptom scores and duodenal mucosal inflammation.
The expected length of participant involvement is approximately 15 weeks, during which they will be required to maintain their usual dietary patterns and continue their gluten-free diet. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial aims to provide valuable insights into the potential benefits of ZED1227 for individuals with celiac disease who do not achieve symptom relief through dietary measures alone.
Treatment
The clinical trial involves the administration of two experimental medications, **CEC02** and **CEC01**, both of which contain the active substance **methyl (E,6S)-7-[[1-[2-(2-ethylbutylamino)-2-oxoethyl]-2-oxopyridin-3-yl]amino]-6-[(3-methylimidazole-4-carbonyl)amino]-7-oxohept-2-enoate**, also known by the synonym **ZED1227**. These medications are provided in the form of hard capsules and are intended for **oral use**. The maximum treatment period for both medications is 15 days. The dosage and frequency of administration are not specified in the provided data. Both CEC02 and CEC01 are chemically derived and are not formulated for pediatric use. The pharmaceutical form and active substance are consistent across both products, ensuring uniformity in the trial's experimental conditions.
In addition to the experimental medications, a **placebo** is used in the study to serve as a comparator treatment. The placebo is designed to match the ZED1227 capsules in appearance, ensuring the double-blind nature of the trial. The placebo is also administered orally, and the treatment period is consistent with that of the experimental medications, lasting up to 15 days. The placebo does not contain any active substance, and its pharmaceutical form is not explicitly detailed in the data provided. The use of a placebo allows for the assessment of the efficacy and tolerability of ZED1227 in subjects with **celiac disease** who continue to experience symptoms despite adhering to a gluten-free diet.
Efficacy
The efficacy of the investigational product ZED1227 in the treatment of **celiac disease** will be assessed through a Phase II, double-blind, randomized, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the change in the Celiac Disease Symptom Diary (CDSD) Gastrointestinal (GI) Specific Symptom Score, which includes symptoms such as diarrhea, abdominal pain, bloating, and nausea. This change will be measured from Baseline Visit B (Week 3) to Visit 5 (Week 15).
Secondary endpoints include the change in the villous height to crypt depth (VH:CrD) ratio from Baseline Visit A (Week 0) to Visit 5 (Week 15), the change in CDSD Non-Stool GI Symptom Score (abdominal pain, bloating, nausea) from Baseline Visit B (Week 3) to Visit 5 (Week 15), and the change in duodenal mucosal inflammation, assessed by the density of CD3-positive intraepithelial lymphocytes (IELs), from Baseline Visit A (Week 0) to Visit 5 (Week 15).
The efficacy parameters will be collected and analyzed at specified timepoints using validated scales and laboratory tests. The trial aims to determine the improvement of celiac disease symptoms in subjects who continue to experience symptoms despite adherence to a gluten-free diet. The trial is designed to provide robust data on the efficacy of ZED1227 in improving the quality of life for individuals with celiac disease.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent
- Men or women between 18 and 80 years of age, inclusively
- Documented initial biopsy-proven diagnosis of celiac disease or, in case of missing histological documentation TG2-IgA > 10 x upper limit of normal (ULN) at diagnosis at least 12 months prior to V0
- Adherence to a gluten-free diet (GFD) for at least 12 months prior to V0
- Human leukocyte antigen DQ (HLA-DQ) typing compatible with celiac disease
- At least one moderate or severe gastrointestinal symptom (i.e., diarrhoea, abdominal pain, bloating, or nausea) during the last 4 weeks prior to Baseline Visit A and last 3 weeks prior to Baseline Visit B as a GI total mean symptom score (measured using CDSD) for the worst 25% of the days of ≥ 2 on a 5-point scale. The interval between Screening Visit and Baseline Visit A must be at least 28 days. If the interval is less than 28 days, this inclusion criterion is not met,
- Biopsy showing VH:CrD ratio of ≤ 2.5 from distal duodenum biopsies in Trial Period A
- Negative diagnosis of Helicobacter pylori infection and no history of eradication within the last two months before biopsy sampling in Trial Period A
- BMI between 17.0 and 35 kg/m², inclusively
- Willingness to follow her/his usual dietary patterns, including eating at restaurants and others’ homes during the trial
- Willingness to maintain current GFD throughout participation in the trial
- Negative pregnancy test in female subjects under 60 years of age at Screening Visit and Baseline Visit B
- Women of child-bearing potential should use a highly effective method of birth control which is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptive pills, combined contraceptive patches and vaginal rings, copper containing intrauterine devices, sexual abstinence or vasectomised partner (see Table 11 for further information on acceptable and unacceptable birth control methods). The investigator is responsible for determining whether the subject has adequate birth control for trial participants
Exclusion Criteria
- Presence of hypo- or hyperthyroidism. A patient with a thyroid stimulating hormone (TSH) level up to 25% higher than ULN or up to 25% lower than the lower limit of normal (LLN) but with normal free triiodothyronine (FT3) and free thyroxine (FT4) levels can be included in the trial. In addition, a patient with a well-controlled thyroid disorder during the previous 3 months can be included
- Abnormal hepatic function (alkaline aminotransferase [ALT] or alkaline phosphatase [ALP] > 2.5 x ULN), liver cirrhosis, or portal hypertension
- Glomerular filtration rate ≤ 60 ml/min/1.73 m²
- Continuous intake of systemic (oral or intravenous) corticosteroids or immunomodulators (e.g., glucocorticoids, cyclosporine, methotrexate, anti-TNF- therapy, anti-integrin therapy, Janus kinase inhibitors), high dose inhaled corticosteroids (> 1000 µg/d of beclomethasone dipropionate or equivalent) during the past 3 months before V0
- Continuous intake of drugs with suspicion of impact on villous atrophy, such as • proton-pump inhibitors (PPIs; permitted at a regular dose equivalent to 20-40 mg/day pantoprazol, esomeprazole or equivalent), • selective serotonin reuptake inhibitors (SSRIs; low to medium dose [10-150 mg Fluvoxamine or equivalent dose of other SSRIs] permitted in case of long-term therapy [at least for 6 months]), • losartan (angiotensin II receptor blockers equivalent to 50 mg losartan permitted except for olmesartan forbidden at any dose) and • mycophenolate1,2 (forbidden at any dose) during the past 2 months before biopsy sampling in Trial Period A; • non-steroidal anti-inflammatory drugs (NSAIDs; maximal daily dose permitted 900 mg for ibuprofen, 500 mg for naproxen and 75 mg for diclofenac, except for one week before biopsy) and • acetylsalicylic acid (max daily dose permitted 100 mg) during the past 4 weeks before biopsy sampling at Baseline Visit A
- Alcohol use > 12 g/d for women, > 24 g/d for men within the past 12 months before screening
- Dual antiplatelet therapy (i.e., acetylsalicylic acid in combination with thienopyridines [clopidogrel, prasugrel, ticlopidine or ticagrelor]) or oral anticoagulants (i.e., warfarin, dabigatran, etexilate, rivaroxaban, apixaban)
- Unwillingness to undergo upper gastrointestinal endoscopy with biopsy at Baseline Visit A and Final/Withdrawal Visit
- Unwillingness to ingest SIGE bars through run-in and treatment period
- Food allergies to nongluten ingredients (tapioca syrup, oats, almonds, rice crisp, chocolate, almond butter, cocoa butter, oat flour, glycerine, sunflower lecithin, salt, and natural flavours) of the SIGE bar or significant symptoms upon ingestion of the gluten-free SIGE bar
- Known hypersensitivity reaction and/or allergy, including anaphylaxis, to wheat and/or gluten
- Patients diagnosed to have confirmed refractory celiac disease type I (RCDI) or II (RCDII), with the exception that patients with a diagnosis of RCDI can be considered for inclusion if they do not have clear signs of T cell monoclonality or atypical T cells (e.g., as revealed by CD3/CD8 immunohistochemistry) and if they do not present with very severe symptoms and/or parameters of significant malabsorption and if they have not received prior treatment with immunosuppressants such as budesonide or azathioprine
- If more than 10% of planned enrolled subjects report a greater than 1 point improvement in PGI-S during Trial Period A, further subjects with > 1 point improvement in PGI-S will be excluded
- Known intolerance/hypersensitivity/resistance to the investigational medicinal product (IMP) and excipients or drugs of similar chemical structure or pharmacological profile
- Doubt about the subject’s cooperation, e.g., because of addiction to alcohol or drugs
- Existing or intended pregnancy or breast-feeding
- Close affiliation with the investigator (e.g., a close relative) or persons working at the study sites (if financially dependent on the investigator) or subject who is an employee of the Sponsor’s company
- Subjects who are institutionalised because of legal or regulatory order
- Participation in another clinical trial of a therapeutic and having received IMP within the last 30 days prior to V0 or within 5 half-lives of IMP (whichever is longer), or participation in another clinical trial related to celiac disease within 12 months prior to screening, or simultaneous participation in another clinical intervention trial, or previous participation in this trial and having received IMP.
- Severe complications of celiac disease (e.g., enteropathy associated T-cell lymphoma [EATL], ulcerative jejunitis, perforation)
- Concomitant diseases of the intestinal tract in addition to celiac disease, such as Crohn’s disease, ulcerative colitis, other forms of inflammatory bowel disease, severe irritable bowel syndrome, microscopic colitis, small intestinal bacterial overgrowth (SIBO), exocrine pancreatic insufficiency; any other active diseases of the intestinal tract (e.g., active, untreated peptic ulcer, esophagitis, gastroesophageal reflux disease) that might, in the investigator’s opinion, interfere with assessment of symptoms of abdominal pain, diarrhoea, or other components of celiac disease
- History or presence of dermatitis herpetiformis
- History or presence of neurological disorders like ataxia or neuropathy (mild neuropathy, related or unrelated to celiac disease, is not a reason for exclusion)
- Any severe concomitant cardiovascular, renal, endocrine (type 1 diabetes mellitus with HbA1C > 8% / 64mmol/mol or hospitalisation or emergency visit for hyperglycaemia or hypoglycaemia within 12 months of screening), or psychiatric disorder or other disease, which in the opinion of the investigator might have an influence on the subject’s compliance or the interpretation of the results
- Any prior invasive malignancy diagnosed within the last 5 years prior to Screening visit. Patients with basal cell carcinoma of the skin completely resected can be included.
- Evidence of relevant systemic disease (e.g., active tuberculosis)
- Concomitant treatment with P-gp inhibitors, concomitant treatment with strong CYP3A4 inhibitors, or use of either P-gp inhibitor or strong CYP3A4 inhibitor within ≤ 5 half-lives of the specific inhibitor prior to screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 30 Apr 2024 | 19 |
 Croatia | Not Recruiting | 30 Apr 2024 | 21 |
 Finland | Recruiting | 30 Apr 2024 | 52 |
 Germany | Recruiting | 30 Apr 2024 | 80 |
 Ireland | Not Yet Recruiting | 30 Apr 2024 | 15 |
 Italy | Not Yet Recruiting | 30 Apr 2024 | 25 |
 Norway | Recruiting | 30 Apr 2024 | 35 |
 Poland | Recruiting | 30 Apr 2024 | 138 |
 Romania | Recruiting | 30 Apr 2024 | 5 |
 Spain | Recruiting | 30 Apr 2024 | 16 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo matching with ZED1227 capsules of Dr. Falk Pharma GmbH | Placebo | N/A | ORAL USE | 000 | 15 | N/A |
CEC02 | Test | CAPSULE, HARD | ORAL USE | 0 | 15 | PRD8266061 |
CEC03 | Test | CAPSULE, HARD | ORAL | 0 | 15 | PRD8246226 |