Evaluation of the efficacy and safety of dual biological therapy in patients with refractory Crohn's disease resistant to induction (FLAMING).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Diseases [C] - Immune System Diseases [C20]

Trial duration

18 Apr 2025 → ongoing

Decision date (initial)

2024-05-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Agencja Badań Medycznych

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To compare the efficacy of infliximab or ustekinumab monotherapy versus combination therapy with infliximab and vedolizumab or ustekinumab and vedolizumab in inducing sustained steroid-free remission in patients with Crohn’s disease after failure of vedolizumab treatment.

Secondary objectives 8

1. To compare the efficacy of infliximab or ustekinumab monotherapy versus combination therapy with infliximab and vedolizumab or ustekinumab and vedolizumab in achieving clinical response in patients with Crohn’s disease after failure of vedolizumab treatment.
2. To compare the efficacy of infliximab or ustekinumab monotherapy versus combination therapy with infliximab and vedolizumab or ustekinumab and vedolizumab in inducing clinical remission in patients with Crohn’s disease after failure of vedolizumab treatment.
3. To compare the efficacy of infliximab or ustekinumab monotherapy versus combination treatment with infliximab and vedolizumab or ustekinumab and vedolizumab in preventing death from Crohn’s disease.
4. To evaluate the corticosteroi-sparing effect of infliximab or ustekinumab monotherapy relative to combination treatment with infliximab and vedolizumab or ustekinumab and vedolizumab in patients with Crohn’s disease.
5. To compare the efficacy of infliximab or ustekinumab monotherapy versus combination treatment with infliximab and vedolizumab or ustekinumab and vedolizumab in achieving endoscopic response in patients with Crohn’s disease.
6. To compare the efficacy of infliximab or ustekinumab monotherapy versus combination treatment with infliximab and vedolizumab or ustekinumab and vedolizumab in achieving endoscopic remission in patients with Crohn’s disease.
7. To evaluate the effect of infliximab or ustekinumab monotherapy versus combination treatment with infliximab and vedolizumab or ustekinumab and vedolizumab on the quality of life of patients with Crohn’s disease.
8. To compare the safety profile of infliximab or ustekinumab versus combination treatment with infliximab and vedolizumab or ustekinumab and vedolizumab in patients with Crohn’s disease.

Conditions and MedDRA coding

Crohn's disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Patient has given written informed consent from to participate in the clinical trial.
2. Patient is male or female aged 18 to 75 years, inclusive.
3. Patient who has CD, confirmed at any time in the past by radiography, histology, or endoscopy, of at least 3 months prior to the randomization.
4. Patients with active Crohn's Disease (CD) who have at least moderately active CD, defined by an absolute CDAI score of at least ≥220, despite 12-weeks of treatment with vedolizumab (VEDO).
5. The following treatments for CD are allowed: a. azathioprine (AZA), 6-mercaptopurine (6-MP) or methotrexate (MTX), if taken at a stable dose for more than 8 weeks prior to the randomization, b. budesonide taken orally at a dose not exceeding 9 mg/day, if taken at a stable dose for at least 2 weeks prior to the randomization, c. other corticosteroids taken orally at a dose not exceeding 20 mg/day of prednisone, if taken at a stable dose for at least 2 weeks prior to the randomization, d. 5-Aminosalicylates (5-ASA), if taken at a stable dose for at least 4 weeks prior to the randomization.
6. For female patients of childbearing potential and male patients and their partners of childbearing potential who agree to use one of the following medically acceptable methods of contraception during the course of the study and for 6 moths following the discontinuation of study drug: - highly effective method of contraception that are user independent, with a failure rate of <1% per year when used consistently and correctly: • implantable progestogen-only hormone contraception associated with inhibition of ovulation; • intrauterine device (IUD); • intrauterine hormone - releasing system (IUS), • bilateral tubal occlusion; • partner after a documented vasectomy (provided that the partner is the sole sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed); - highly effective method of contraception that are user dependent, with a failure rate of <1% per year when used consistently and correctly: • progestogen-only hormone contraception associated with inhibition of ovulation (oral or injectable) • combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: - oral - intravaginal - transdermal - injectable The use of the aforementioned methods also applies to women and men who have had surgical sterilization within 6 months prior to the date of informed consent. A woman of childbearing potential is defined as a woman from the onset of her first menarche and until becoming postmenopausal (defined as age >45 and no menses for at least 12 months without an alternative medical cause), unless permanently sterile (permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral oophorectomy). Menopausal females must have experienced their last period more than 12 months prior to the date of informed consent to be classified as not childbearing potential. Women and men who have had surgical sterilization more than 6 months prior to the date of informed consent are considered as not childbearing potential.

Exclusion criteria 20

1. Allergies to any of the excipients of infliximab or ustekinumab or any other murine and/or human proteins or has hypersensitivity to immunoglobulin products.
2. Patient who has received any of following treatments: a. Within 2 weeks prior to randomization: - budesonide taken orally in excess of 9 mg/day, - other GCSs taken orally in excess of 20 mg/day prednisone, - GCSs administered parenterally, - antibiotics for the primary treatment of CD (e.g., ciprofloxacin, metronidazole) b. Within 3 weeks prior to the randomization: - apheresis (e.g., Adacolumn apheresis), c. Within 4 weeks prior to the randomization administration of parenteral antibiotics d. Within 8 weeks prior to the randomization initiation of treatment with the following drugs: - azathioprine, - 6-mercaptopurine, - methotrexate.
3. Patient who has received any of following treatments due to CD or other disease: a. within 4 weeks prior to randomization: janus kinase (JAK) inhibitors, including but not limited to tofacitinib and baricitinib, b. within 8 weeks prior to randomization: cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, c. within 12 months prior to randomization: alkylating agents, d. ever: infliximab, ustekinumab.
4. Currently require or are anticipated to require surgical intervention for CD during the study.
5. Abdominal surgery for, including but not limited to, active gastrointestinal bleeding, peritonitis, intestinal obstruction, gastrointestinal resection, or intra-abdominal or pancreatic abscess requiring surgical drainage within 6 months prior to the randomization.
6. Extensive colonic resection (subtotal and total colectomy) prior to the randomization.
7. History of more than 3 small-bowel resection procedures.
8. Stoma (e.g., ileostomy or colostomy) within 6 months prior to the randomization.
9. Nonautologous stem cell therapy (e.g. Prochymal) within 12 months prior to the randomization.
10. Use of total parenteral nutrition within a month prior to the randomization.
11. Use of exclusive enteral nutrition for more than 3 consecutive days within a month or any single day of exclusive enteral nutrition within 2 weeks prior to the randomization.
12. Live or live - attenuated vaccine within 4 weeks prior to the randomization.
13. Abnormalities in laboratory tests performed at screening: a. Serum creatinine ≥ 1.5 × upper limit of normal (ULN) or an estimated creatinine clearance level (eGFR) ≤ 50 ml/min (calculated from the Cockcroft-Gault formula), b. Serum alanine aminotransferase ≥ 2.0 × ULN, c. Serum aspartate aminotransferase ≥ 2.0 × ULN, d. Serum total bilirubin ≥ 1.5 × ULN, e. Hemoglobin < 8.5 g/dl (SI units: < 85 g/l or 5.28 mmol/l ), f. White blood cell count < 3.5 × 103 cells/μl (SI units: <3.5×109 cells/l), g. Neutrophil count < 1.5 × 103 cells/μl (SI units: <1.5×109 cells/l), h. Platelet count < 100 × 103 cells/μl (SI units: <100×109 cells/l). i. Positive HBsAg result, j. Positive HBV DNA result, k. Positive HCV RNA result, l. Positive anti-HIV result, m. Positive or twice inconclusive Quantiferon-TB Gold test result.
14. Patient who has a current or history of any of the following infections: a. Known infection with hepatitis B or hepatitis C (active or carrier state). However, a patient who is without cirrhosis of liver and recovered from a past hepatitis B or hepatitis C infection can be enrolled. A patient with a history of cured hepatitis B or C who does not have cirrhosis of liver can be enrolled but the following conditions must be met on screening: -a negative HBsAg and HBV DNA result for a patient with hepatitis B, - a negative HCV RNA result in the case of a patient with hepatitis C. b. Known infection with human immunodeficiency virus (HIV). c. Acute infection requiring oral antibiotics within 2 weeks or parenteral injection within 4 weeks prior to the randomization. d. Recurrent hemiplegia. e. Other recurrent or chronic infection, significant in the investigator’s opinion, within 6 weeks prior to the randomization. f. Current or past granulomatous infections or opportunistic infections (e.g., Pneumocystis carinii, aspergillosis, or mycobacteriosis [infection caused by nontuberculous mycobacteria]) or invasive fungal infection (e.g., histoplasmosis). g. Known cytomegalovirus infection within 6 months prior to the randomization. h. Evidence of Clostridioides difficile toxin in stool within 3 months prior to the randomization. i. Patient who has a current diagnosis of active TB or a history of active TB. Patient who has any evidence of history of active TB cannot be enrolled despite sufficient documentation of complete resolution of active TB. j. Patient who has had exposure to person(s) with active TB (e.g., first-degree relative, co-worker, roommate). k. Current diagnosis of latent TB at screening (defined as a positive Quantiferon-TB-Gold without clinical signs of active tuberculosis and with a negative examination of chest x-ray from the qualifying visit for vedolizumab treatment). k. Other serious infections, in the investigator’s opinion, within 6 months prior to the randomization.
15. Medical condition including 1 or more of the following a. Diagnose of UC (ulcerative colitis) or indeterminate colitis. b. Short bowel syndrome. c. Evidence of fixed symptomatic stenosis or obstruction of the large or small intestine. d. Active entero-vesical, entero-retroperitoneal, entero-cutaneous or entero-vaginal fistulae within 6 months prior to the randomization. Entero-enteral fistulae without clinically significant symptoms in the invesigator’s opinion and anal fistulae without draining problems are allowed. e. Body mass index ≥ 35 kg/m2. f. Uncontrolled diabetes mellitus. g. Uncontrolled hypertension (as defined by systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg). h. A known malignancy within 5 years prior to the randomization, except completely excised and cured squamous carcinoma in situ of the uterine cervix, cutaneous basal cell carcinoma, or cutaneous squamous cell carcinoma. i. History of lymphoma, lymphoproliferative disease, or bone marrow hyperplasia. j. New York Heart Association (NYHA) class III or IV heart failure, severe uncontrolled cardiac disease (unstable angina or clinically significant electrocardiogram [ECG] abnormalities), or myocardial infarction within 6 months prior to the randomization. k. History of organ transplantation, including corneal graft/transplantation. l. Any uncontrolled, clinically significant respiratory disease in the investigator’s opinion, including but not limited to chronic obstructive pulmonary disease, asthma, bronchiectasis, or pleural effusion. m. Previous diagnosis or symptoms suggestive of demyelinating disorders, including multiple sclerosis and Guillain-Barré syndrome. n. Any condition significantly affecting the nervous system (e.g., neuropathic conditions or nervous system damage). o. Any other serious acute or chronic medical, or psychiatric conditions that may increase the risk associated with study participation or investigational product administration or that may interfere with the interpretation of study results.
16. Current or history of alcohol abuse within 12 months prior to the randomization.
17. Treatment with any other investigational device or medical product within 4 weeks prior to the randomization or 5 half-lives of the drug, whichever is longer.
18. Female patients who are currently pregnant or planning to become pregnant within 6 months of the last dose of study drug.
19. Female patients who are currently breastfeeding planning to breastfeed within 6 months of the last dose of study drug.
20. Lack of cooperation from the patient.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of sustained corticosteroid-free remissions at week 52, sustained from week 8 onward with a maximum 11-week regimen of corticosteroids tapering. Clinical remission defined as an absolute CDAI score <150 points.

Secondary endpoints 14

1. Percentage of clinical response at Week 8, Week 22 and Week 52, defined as CDAI-100 response,, i.e., a decrease in CDAI score of 100 points or more from the baseline value.
2. Percentage of clinical response at Week 8, Week 22 and Week 52, defined as CDAI-70, i.e. a decrease in CDAI score of 70 points or more form the baseline value.
3. Percentage of clinical remission at Week 8, defined as an absolute CDAI score of < 150 points.
4. Percentage of deaths from Crohn’s disease at Week 8, Week 22 and Week 52. 5. The cumulative dose of corticosteroids used during the current flare of Crohn’s disease at Week 52.
5. The cumulative dose of corticosteroids used during the current flare of Crohn’s disease at Week 52.
6. Percentage of patients who achieved endoscopic remission at Week 8, Week 22 and Week 52 . Endoscopic remission is defined as (all conditions must be met): - SES-CD score ≤ 4 points and - SES-CD score with at least 2 points reduction from baseline value and - SES-CD subscores ≤ 1 point in all individual component.
7. Percentage of patients who achieved an endoscopic response at Week 8, Week 22 and Week 52, defined as a 50% reduction in SES-CD score from baseline value.
8. Change from baseline value in quality of life measured by SIBDQ, PROMIS-29 v.2.1, WPAI:GH v.2.2 and PSQI questionnaires, at Week 8, Week 22 and Week 52.
9. Occurrence of severe adverse events at Week 8, Week 22 and Week 52.
10. Occurrence of non-severe adverse events at Week 8, Week 22 and Week 52.
11. Occurrence of death from any cause at Week 8, Week 22 and Week 52.
12. Occurrence of MACE events, defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, at Week 8, Week 22 and Week 52.
13. Occurrence of tuberculosis at Week 8, Week 22 and Week 52.
14. Occurrence of hemiplegia at Week 8, Week 22 and Week 52.

Investigational products

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

Test 4

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Sponsor organisation

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Address

Ulica Szaserow 128

City

Warsaw

Postcode

04-141

Country

Poland

Scientific contact point

Organisation

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Contact name

Klinika Gastroenterologii i Chorób Wewnętrznych

Public contact point

Organisation

Wojskowy Instytut Medyczny Panstwowy Instytut Badawczy

Contact name

Klinika Gastroenterologii i Chorób Wewnętrznych

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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