Celecoxib for Prevention of Progression in Peutz-Jeghers Syndrome

Official title

Celecoxib for Prevention of Progression in Peutz-Jeghers Syndrome: A Double-blind, Randomized, Placebo-controlled Trial

Overview

The Peutz-Jeghers Syndrome (PJS) is a rare autosomal dominant syndrome characterized by mucocutaneous pigmentations, multiple gastrointestinal hamartomatous polyps, and an elevated risk of developing malignancies. Patients with PJS often experience recurrent gastrointestinal polyps that gradually increase in number and size, requiring repeated treatments. As the disease progresses, most patients are forced to undergo multiple surgical or endoscopic treatments. Small bowel polyps develop in 60-90% of patients with PJS, and intussusception occurs in 65% of these patients. Currently, on-demand surgery or scheduled endoscopic polypectomy is the standard of care for the management of small bowel polyps, and among patients who have undergone an initial surgery, reoperation is performed in up to 40% within 5 years. In addition, 8-40% of patients develop small bowel polyp-related complications even with multiple endoscopic treatments. However, surgery and endoscopic treatments are associated with complications, including short bowel syndrome, intestinal adhesions, bowel perforation and bleeding, and health-related quality of life. These problems often lead to decreased patient compliance and even treatment resistance, which increases the risk of disease progression. Because surgical and endoscopic treatment do not completely eliminate the potential for future polyps or extraintestinal neoplasms, there is an unmet medical need for the identification and use of pharmacologic agents to delay endoscopic or surgical interventions. Cyclooxygenase (COX) is overexpressed in hamartomatous polyp tissue from PJS individuals, which may provide an avenue for possible effective chemoprevention of polyp formation and growth in PJS. Celecoxib, a COX-2 inhibitor, has been shown to reduce polyp burden by 54% in PJS model mice. In addition, the study evaluated the treatment effect of celecoxib on six patients with PJS, two of whom experienced a reduction in gastric polyp burden after six months. These findings provide preliminary evidence that celecoxib may delay the progression of PJS as a potential pharmacological prophylaxis. Investigators plan to conduct a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of celecoxib, and they will use a time-to-event analysis with a composite efficacy end point to determine whether celecoxib can delay disease progression or reduce the need for important endoscopic or surgical procedures in patients with PJS.

Interventions

• Drug Celecoxib 400mg
  Participants in the interventional group receive 200 mg celecoxib twice daily for 6 months
• Drug Placebo
  Participants in the control group receive identically appearing placebo twice daily for 6 months

Primary outcome measures

• The progression of small bowel disease (composite end point) [Time frame: 2 years]

Secondary outcome measures (9)

• Drug-related adverse events (Severity assessed according to CTCAE 5.0) [Time frame: 2 years]
• Burden of gastroduodenal and colonic polyps based on gastrointestinal endoscopy (mean or median diameter of 5 largest polyps) [Time frame: 2 years]
• Other complications of PJS polyps [Time frame: 2 years]
• European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30（EORTC QLQ-C30） [Time frame: 2 years]
• European Organization for Research and Treatment of Cancer Quality of Life Questionnaire ⁃ Colorectal Cancer 29（EORTC QLQ ⁃CR29） [Time frame: 2 years]
• EuroQol Five Dimensions Questionnaire（EQ-5D） [Time frame: 2 years]
• Number of enteroscopy or surgical treatments and related complications [Time frame: 2 years]
• Incidence of gastrointestinal and other systemic tumors [Time frame: 2 years]
• The mortality rate [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

\- Patients with PJS ≥ 8 years of age

Diagnostic criteria for PJS: meeting any of the following criteria or presence of an STK11 gene variant:

• Two or more histologically confirmed PJS hamartomatous polyps;
• Any number of PJS polyps detected in an individual with a family history of PJS in close relative(s);
• Characteristic mucocutaneous pigmentation in an individual with a family history of PJS in close relative(s);
• Any number of PJS polyps in an individual with characteristic mucocutaneous pigmentation.

Exclusion criteria

• Allergy to NSAIDs;
• Long-term use of any dose of NSAIDs, including aspirin or celecoxib, within 6 months prior to enrollment (willing to undergo a 3-month washout period to restore eligibility);
• Imaging indicate small intestinal polyps ≥ 3 cm in diameter, intestinal intussusception, intestinal obstruction or intestinal tumor at the time of enrollment;
• Surgical treatment for small intestinal polyps within 2 years prior to enrollment;
• Anticipated small bowel resection due to severe polyps within 6 months of enrollment;
• Receiving other medications for gastrointestinal polyps;
• Peptic ulcer within 3 months prior to enrollment;
• Unstable cardiorespiratory condition;
• Serious renal, hepatic or haematological dysfunction (creatinine >1.5 × ULN; ALT >1.5 × ULN, AST >1.5 × ULN, ALP >1.5 × ULN, TBIL >2 × ULN; haemoglobin <10 g/dL, platelet count <100,000/mL, white blood cells <3000/mL) or other systemic diseases are unsuitable for participation in this study;
• Pregnancy or breastfeeding;
• Unwilling or unable to sign the informed consent form

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

China · 1 center

• Xijing Hospital of Digestive Diseases, Air Force Military Medical University — Xi'an

Identifiers

NCT: NCT06722534 · KY20242368

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗