A study to discover if ZED1227 can improve continued celiac disease symptoms despite a gluten-free diet

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Dr. Falk Pharma GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

29 May 2024 → ongoing

Decision date (initial)

2024-04-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Dr. Falk Pharma GmbH

External identifiers

EU CT number

2023-506150-21-00

EudraCT number

2017-002241-30

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Others

To assess multiple doses of ZED1227 capsules vs placebo for efficacy in: Improvement of celiac disease symptoms as assessed by Celiac Disease Symptom Diary (CDSD) in celiac disease subjects experiencing symptoms and having mucosal damage on a gluten-free diet.

Secondary objectives 1

1. To assess the efficacy of ZED1227 capsules for: • Changes in duodenal mucosal morphology as measured by morphometry (villous height to crypt depth, VH:CrD), • Changes in the severity of non-stool gastrointestinal (GI) symptoms (abdominal pain, bloating, nausea) as assessed by CDSD. To assess the safety and tolerability of ZED1227 in terms of adverse events (AEs) and laboratory parameters

Conditions and MedDRA coding

Celiac Disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Signed informed consent
2. Men or women between 18 and 80 years of age, inclusively
3. 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
4. Adherence to a gluten-free diet (GFD) for at least 12 months prior to V0
5. Human leukocyte antigen DQ (HLA-DQ) typing compatible with celiac disease
6. 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,
7. Biopsy showing VH:CrD ratio of ≤ 2.5 from distal duodenum biopsies in Trial Period A
8. Negative diagnosis of Helicobacter pylori infection and no history of eradication within the last two months before biopsy sampling in Trial Period A
9. BMI between 17.0 and 35 kg/m², inclusively
10. Willingness to follow her/his usual dietary patterns, including eating at restaurants and others’ homes during the trial
11. Willingness to maintain current GFD throughout participation in the trial
12. Negative pregnancy test in female subjects under 60 years of age at Screening Visit and Baseline Visit B
13. 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 27

1. 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
2. Abnormal hepatic function (alkaline aminotransferase [ALT] or alkaline phosphatase [ALP] > 2.5 x ULN), liver cirrhosis, or portal hypertension
3. Glomerular filtration rate ≤ 60 ml/min/1.73 m²
4. 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
5. 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
6. Alcohol use > 12 g/d for women, > 24 g/d for men within the past 12 months before screening
7. 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)
8. Unwillingness to undergo upper gastrointestinal endoscopy with biopsy at Baseline Visit A and Final/Withdrawal Visit
9. Unwillingness to ingest SIGE bars through run-in and treatment period
10. 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
11. Known hypersensitivity reaction and/or allergy, including anaphylaxis, to wheat and/or gluten
12. 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
13. 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
14. Known intolerance/hypersensitivity/resistance to the investigational medicinal product (IMP) and excipients or drugs of similar chemical structure or pharmacological profile
15. Doubt about the subject’s cooperation, e.g., because of addiction to alcohol or drugs
16. Existing or intended pregnancy or breast-feeding
17. 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
18. Subjects who are institutionalised because of legal or regulatory order
19. 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.
20. Severe complications of celiac disease (e.g., enteropathy associated T-cell lymphoma [EATL], ulcerative jejunitis, perforation)
21. 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
22. History or presence of dermatitis herpetiformis
23. History or presence of neurological disorders like ataxia or neuropathy (mild neuropathy, related or unrelated to celiac disease, is not a reason for exclusion)
24. 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
25. 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.
26. Evidence of relevant systemic disease (e.g., active tuberculosis)
27. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in CDSD GI Specific Symptom Score (diarrhoea, abdominal pain, bloating, nausea) from Baseline Visit B (V2, Wk 3) to V5 (Wk 15).

Secondary endpoints 3

1. Change in VH: CrD from Baseline Visit A (V1, Wk 0) to V5 (Wk 15),
2. Change in CDSD Non-Stool GI Symptom Score (abdominal pain, bloating, nausea) from Baseline Visit B (V2, Wk 3) to V5 (Wk 15),
3. Change in duodenal mucosal inflammation measured as the density of CD3-positive intraepithelial lymphocytes (IELs) from Baseline Visit A (V1, Wk 0) to V5 (Wk 15).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dr. Falk Pharma GmbH

Sponsor organisation

Dr. Falk Pharma GmbH

Address

Leinenweberstrasse 5, Hochdorf Hochdorf

City

Freiburg Im Breisgau

Postcode

79108

Country

Germany

Scientific contact point

Organisation

Dr. Falk Pharma GmbH

Contact name

Clinical Research and Development, Dr. Falk Pharma GmbH

Public contact point

Organisation

Dr. Falk Pharma GmbH

Contact name

CTIS - Scientific Request, Dr. Falk Pharma GmbH

Third parties 9

Locations

9 EU/EEA countries · 60 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 88 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

12 submissions — initial application plus substantial / non-substantial modifications