Clinical trial NCT05871333: Effect of Losartan on the Incidence and Severity of Chemotherapy-Induced Mucositis in Gastrointestinal Cancer Patients
Official title: Effect of Losartan on the Incidence and Severity of Chemotherapy-Induced Mucositis in Gastrointestinal Cancer Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Chemotherapy
Colorectal Cancer
Intestinal Mucositis
Oral Mucositis
Keywords: Losartan
Colorectal Cancer
Chemotherapy-Induced Mucositis
Lead sponsor: Ain Shams University
Sponsor class: OTHER
First posted: 2023-05-23
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Group I: Patients will receive only their standard therapy for 4 months. Group II: will receive the studied drug orally in addition to their standard therapy
Primary purpose: PREVENTION

Brief summary: Mucositis is a common and clinically significant side effect of both anticancer chemotherapy and radiation therapy that can affect any portion of the gastrointestinal tract. Not only associated with an adverse symptom profile, but also it may limit patients' ability to tolerate treatment if not adequately prevented and managed. Moreover, it may be associated with secondary local and systemic infection and poor health outcomes, and generates additional use of healthcare resources resulting in additional costs.

Based on study of 38 patients of mean age sixty-one years old diagnosed with colorectal carcinoma were included to evaluate gastrointestinal adverse effect with different schedules of FOLFOX. Incidence of oral mucositis with FOLFOX-4 Is 76%, FOLFOX-6 is 62%, mFOLFOX-6 is 79% and FOLFOX-7 is 93%

Chemotherapy-induced mucositis is commonly described as a five-phase sequence:

initiation (0-2 days),upregulation and activation of messengers (2-3 days), signal amplification (2-5 days), ulceration with inflammation (5-14 days) and healing (14-21 days)

According to the model introduced by some studies the primary inducer involved in unleashing mucosal injury upon chemotherapy is the production of reactive oxygen species (ROS), leading to tissue inflammation and mucositis induction.

Inflammatory signaling pathways are upregulated during high reactive oxygen species states which further contribute to cytotoxicity. leading to the third step in the oral mucositis pathway. In this inflammatory phase, cytokines including Tissue Necrosis Factor alpha (TNF-α), prostaglandins, Nuclear factor Kappa β (NF-кβ), and interleukin (IL) 1β are released.

The cytotoxic effects of chemotherapy, inflammation, and reactive oxygen species-mediated DNA damage result in gradual apoptosis of mucosal epithelial cells. Ulcerative sites become relatively neutropenic which predisposes them to bacterial and yeast infections. These bacterial toxins further simulate the underlying inflammatory state through release of additional cytokines.

It is necessary to emphasize that oral mucositis is frequently documented only in its advanced phases owing to the requirements for clinical therapy and assistance. Therefore, the search for new active ingredients that could be used in the prevention (and even treatment) of oral and intestinal mucositis is of utmost importance.

Detailed description: in this study Losartan, a AT1 angiotensin 2 receptor blockers (ARB), used clinically for antihypertensive purposes, has anti-inflammatory effects widely described in the literature.

Losartan has been shown to reduce pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and the activation of nuclear transcription factor (NF-κB), in addition to an antioxidant effect in different inflammatory diseases as neuropathic pain in patients with paclitaxel- induced peripheral neuropathy.

Studies have already shown that angiotensin 2 pathway modulators have a protective effect on oral and intestinal mucositis in rats.

Patients meeting the study inclusion criteria will be educated firmly about the disease details and all information about the drug, then will be assigned to one of two groups, the control group or the intervention group.

The two groups will undergo baseline evaluation at the beginning of the study including Demographic data collection: Age, gender, weight, height, BSA, Risk factors related to mucositis, Medical history and Comorbidities reporting as HTN, DM and others, Vital signsas Blood pressure and pulse recording, Social history and Smoking status and Clinical assessment for confirmation of absence of mucositis and examination of oral mucous membrane and gut functions (bowel habits) Weekly for assessment of the following: occurrence and severity of OM and IM, Pain assessment will be done using the NRS score and through patient interview, occurrence and severity of dysphagia and Need for supportive management e.g. Painkillers and anti-diarrhea.

Every cycle for the need for hospitalization due to oral or intestinal symptoms or any unplanned chemotherapy breaks due to oral or intestinal toxicity in both groups.

In between cycles via phones for any side effects encountered by patients in both groups due to the administered drug (Losartan). Patients will be given a side effects reporting card for follow up if any side effect occurred during treatment. And Quality of Life assessment by Functional Assessment of Cancer Therapy- General (FACT-G).

By the end of cycle 8, all patients in both groups will be reassessed for all laboratory and clinical evaluations.

Eligibility criteria: Inclusion Criteria:

1. Male or female patients aged 18 years old or more.
2. Patients diagnosed with gastrointestinal cancer eligible for chemotherapy
3. Eastern Cooperative Oncology Group (ECOG) performance ≤ 2.
4. Platelet count more than 100 × 10\^9/L.
5. Absolute neutrophil count: greater than 1.5 × 10\^9/L.
6. Aspartate aminotransferase level up to 2.5 times the upper limit normal.
7. Serum bilirubin level not more than 1.5 times the institutional upper limit normal.
8. Serum creatinine levels up to 1.5 mg% and 1.4 mg% for males and females respectively.

Exclusion Criteria:

1. Currently taking an angiotensin converting enzyme inhibitor (ACEi) or Angiotensin receptor blocker (ARB)
2. Prior reaction or intolerance to an ARB or ACE inhibitor, including but not limited to angioedema.
3. Pregnant or breastfeeding women.
4. Females in child bearing age not currently taking a protocol allowed version of contraception: intrauterine device, Depo-formulation of hormonal contraception.
5. Patient reported history or electronic medical record history of kidney disease, defined as:

   Any history of dialysis. History of chronic kidney disease stage IV. Estimated Glomerular Filtration Rate (eGFR) of \< 30ml/min/1.73 m2 Other Kidney disease that in the opinion of investigator, would affect Losartan Clearance.
6. Patient reported dehydration and significantly decreased urine output in the past 72 hours.
7. Most recent systolic blood pressure prior to enrollment \<110 mmHg.
8. Current participation in any other clinical investigation.
9. Currently taking any drug contraindicated with Losartan administration.

Primary outcomes:
measure: Change in Occurrence of oral mucositis
timeFrame: monthly for 6 months
measure: change in Severtity of Oral Mucositis
timeFrame: monthly for 6 months
measure: change in severity of intestinal mucositis
timeFrame: monthly for 6 months
Secondary outcomes:
measure: Evaluation of cancer control by Ultrasound
timeFrame: at Baseline and at week 24 ( end of study)
measure: Quality of life questionnaire
timeFrame: monthy for 6 months
measure: Laboratory evaluation of TNF-α level
timeFrame: baseline and at week 16
measure: Laboratory evaluation of Interleukin-1β level
timeFrame: Baseline and at week 16
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: Hospital
Study officials:
affiliation: Ain Shams University
name: Amira Y mohamed
role: PRINCIPAL_INVESTIGATOR
References: