Autologous Platelet-rich Plasma (PRP) and Thrombin Coagulum for the Topical Treatment of Rectal Mucosal Ulcers

Study Overview
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Brief Summary
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Ulcerative colitis (UC) is a chronic persistent inflammatory disease. The lesions are mainly confined to the large intestine and continuously affect the rectum and part or all of the colon. Its histological characteristics are diffuse neutrophil infiltration in the lamina propria of the colon mucosa, mucosal erosion, ulcer, cryptitis, and crypt abscess. The most common clinical manifestations are abdominal pain, diarrhea, and bloody mucopurulent stool, accompanied by extraintestinal manifestations such as mouth, skin, joints, and eyes. Severe lesions can be complicated by toxic megacolon, intestinal perforation, lower gastrointestinal hemorrhage, intraepithelial neoplasia, and cancer, so surgical treatment is necessary. Studies have reported that UC patients have a 10-year cumulative recurrence risk of 70%-80%, nearly 50% of patients require UC-related hospitalization, and the 5-year risk of re-hospitalization is   50%. The 5-year and 10-year cumulative risk of patients undergoing colectomy is 10%-15%, which dramatically endangers the health of patients and reduces the quality of life of patients. Currently, the commonly used medical treatment drugs for UC patients include 5-aminosalicylic acid, topical and systemic glucocorticoids, immunomodulators, anti-tumor necrosis factor drugs, and other biological agents. The most commonly used optimization methods are drug escalation therapy and combining drugs with different mechanisms. The real-world data results of an initial population-based cohort study from six Asian countries showed that the endoscopic mucosal healing rate of patients with ulcerative colitis in the first year of diagnosis was 38.2%, and the histological mucosal healing rate was 23.1%. It can be expected that the mucosal healing rate of patients with moderate to severe UC may be lower. Long-term chronic recurrent diseases may lead to poorer quality of life, extended hospital stays, heavier financial burdens, and more physical and mental pain. Therefore, optimizing the treatment plan for patients with moderate to severe UC needs more exploration and research. Autologous Platelet-rich plasma (A-PRP) is A platelet-rich concentrate obtained by centrifugation of whole blood. As a concentrated source of autologous platelets, they contain a large number of Growth factors (GF) and cytokines, such as platelet-derived Growth factor (PDGF), transforming growth factor β(TGF-β), vascular endothelial growth factor (VEGF) and epithelial growth factor (EGF), which regulate cell function. Such as attachment, macrophage migration, proliferation, and differentiation, promote extracellular matrix accumulation and ultimately improve tissue healing and regeneration. At the same time, A-PRP has A lower risk of adverse reactions such as immune rejection and allergy due to its isolation from autologous blood. After PRP is induced by activators such as calcium and thrombin, activated platelets degranulate immediately and secrete multiple high concentrations of growth factors. 70% of the growth factors can be released within 10 minutes of activation, and more than 95% can be released within the first hour. Platelet-rich Gel (PG), which can embed growth factors to improve clinical efficacy, keeps platelets and their release products in the target wound area and promotes healing. Although the safety and efficacy of PRP still need to be fully confirmed by large-scale clinical trials, its sound effect has been verified in many clinical practices and basic scientific research in cell culture and animal models. At present, it mainly includes the treatment of oral and maxillofacial external, musculoskeletal system, plastic skin, and chronic wounds (such as pressure ulcers, venous leg ulcers, diabetic foot ulcers, etc.). They can be mixed into bone grafts, sprayed on soft tissue surfaces as a biofilm, or made into eye drops. The use of PRP in intestinal mucosal ulcers has rarely been reported. There are no prospective randomized studies of its clinical use in patients with ulcerative colitis. Therefore, we planned to conduct a prospective, randomized, double-blind, controlled clinical trial to investigate the efficacy and safety of repeated treatment with autologous platelet-rich plasma gel on an intestinal mucosal ulcer in patients with moderate to severe UC involving the rectum in Xijing Hospital, China IBD Regional Center. To provide a new option for remission induction therapy in patients with moderate to severe ulcerative colitis.

Official Title
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Safety And Efficacy Study of Autologous Platelet-rich Plasma (PRP) and Thrombin Coagulum for the Topical Treatment of Rectal Mucosal Ulcers

Conditions
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Ulcerative Colitis Chronic Moderate, Ulcerative Colitis Chronic Severe, Rectal Ulcer

Intervention / Treatment
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* Other: Autologous Platelet-rich Plasma (PRP) and Thrombin Coagulum Treatment
* Other: Autologous Platelet-poor Plasma (PPP) and Thrombin Coagulum Treatment
* Drug: Mesalazine Suppository Treatment
* Biological: Infliximab Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Platelet ≥150×10^9g/L, hemoglobin ≥60g/L; Patients with ulcerative colitis were diagnosed according to the diagnostic criteria of ulcerative colitis in the 2018 China's National consensus on the diagnosis and treatment of inflammatory bowel disease; Patients with moderate to severe ulcerative colitis involving the rectum or refractory distal rectal ulcerative colitis (modified Mayo score ≥6 and endoscopic Mayo score ≥2); Patients with ulcerative colitis who were initially treated with infliximab (according to a regular intravenous infusion schedule of 0w, 2w, 6w, and then every 8w); Patients who were able and willing to adhere to the study protocol provided signed, dated, written informed consent. Exclusion Criteria: Patients with platelet-related bleeding diseases (such as Henoch-Schonlein purpura, coagulopathy, primary/secondary thrombocytopenia, etc.); Medications with anticoagulant effects such as nonsteroidal anti-inflammatory drugs, heparin, coumarin, warfarin, aspirin, etc. (acetaminophen was used to treat discomfort during the study period); Patients using mesalazine enema solution during treatment; Patients with active infection of intestinal or other extra-intestinal organs (hepatitis, active tuberculosis, etc.); Patients with known hypersensitivity to calcium gluconate and thrombin Patients who may require immediate surgical treatment; Pregnant or nursing mothers; Patients with severe liver and kidney dysfunction, heart failure or other serious systemic diseases; Any conditions that prevent the completion of the study or interfere with the analysis of the study results, including drug or alcohol abuse history, smoking abstinence, mental illness or poor compliance, and clear immune system (including HIV infection), blood system or cancer related diseases; Patients who withdraw consent; Patients enrolled in other clinical trials within 3 months prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Platelet-rich Plasma (PRP) Gel Treatment Group<br>Rectal 10ml platelet rich plasma gel enema + infliximab standard treatment at fixed time every day for seven consecutive days | Other: Autologous Platelet-rich Plasma (PRP) and Thrombin Coagulum Treatment<br>* 10 mL PRP and thrombin coagulum gel was administered every night for seven consecutive days by the same IBD specialist. Before the intervention, the patients had to defecate. The prepared PRP gel was injected into the external opening of the rectum using the same syringe, and the patient was kept in the Trendelenburg position to ensure that the therapeutic drug remained in place under gravity. The normal supine position was returned after 15 minutes to minimize PRP leakage. The outflow was observed, and the amount of outflow was recorded.<br>Biological: Infliximab Treatment<br>* Patients, in every arm, all receive infliximab (300 mg iv at 0, 2, 6 weeks, and then every eight weeks).<br>|
| Sham Comparator: Platelet Poor Plasma (PPP) Gel Treatment Group<br>Rectal 10ml PPP gel enema + infliximab standard treatment for 7 consecutive days | Other: Autologous Platelet-poor Plasma (PPP) and Thrombin Coagulum Treatment<br>* 10 mL PPP and thrombin coagulum gel was administered every night for seven consecutive days by the same IBD specialist. Before the intervention, the patients had to defecate. The prepared PPP gel was injected into the external opening of the rectum using the same syringe, and the patient was kept in the Trendelenburg position to ensure that the therapeutic drug remained in place under gravity. The normal supine position was returned after 15 minutes to minimize PPP leakage. The outflow was observed, and the amount of outflow was recorded.<br>Biological: Infliximab Treatment<br>* Patients, in every arm, all receive infliximab (300 mg iv at 0, 2, 6 weeks, and then every eight weeks).<br>|
| Active Comparator: Mesalazine Suppository Treatment Group<br>Patients were given 1g mesalazine suppository and infliximab daily for 7 consecutive days | Drug: Mesalazine Suppository Treatment<br>* For patients receiving mesalazine suppositories, the intervention was inserted through the anus with a disposable sanitary finger to the point of slight loss of resistance. To facilitate intervention, moisturize with water or cream. If the drug drains within 10 minutes, it should be re-inserted. The swelling at the local injection site on each group's intervention day was recorded.<br>Biological: Infliximab Treatment<br>* Patients, in every arm, all receive infliximab (300 mg iv at 0, 2, 6 weeks, and then every eight weeks).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endoscopic response rate of local treatment with autologous platelet-rich plasma gel | Endoscopic response rate of local treatment with autologous platelet-rich plasma gel in patients with moderate to severe ulcerative colitis involving the rectum. | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endoscopic remission rate of local treatment with autologous platelet-rich plasma gel | Endoscopic remission rate of local treatment with autologous platelet-rich plasma gel in patients with moderate to severe ulcerative colitis involving the rectum. | 1 week and 14 weeks | 
| Clinical response rate of PRP-thrombin coagulum treatment on Rectal Mucosal Ulcers | The clinical response rate will be analyzed. | 1 week and 14 weeks | 
| Clinical remission rate of PRP-thrombin coagulum treatment on Rectal Mucosal Ulcers | The clinical remission rate will be analyzed. | 1 week and 14 weeks | 
| Inflammatory parameter alteration with PRP-thrombin coagulum treatment on Rectal Mucosal Ulcers | The erythrocyte sedimentation rate will be analyzed. | 1 week, 2 weeks, 6 weeks, and 14 weeks | 
| Inflammatory response alteration with PRP-thrombin coagulum treatment on Rectal Mucosal Ulcers | The C-reactive protein concentration will be analyzed. | 1 week, 2 weeks, 6 weeks, and 14 weeks | 
| Incidence of Adverse Events | Adverse events will reported at the start and throughout the treatment period. | 1 week, 2 weeks, 6 weeks, and 14 weeks |