A Study of Chlorophyllin or Placebo With Standard Treatment for Late Radiation Induced Luminal Gastrointestinal Tract Bleeding

Late radiation-induced gastrointestinal (GI) bleeding is a chronic complication that may develop months to years after radiotherapy for abdominal, pelvic, or mediastinal malignancies. Patients may experience persistent GI bleeding, anemia, recurrent blood transfusions, impaired quality of life, and repeated invasive procedures. Existing treatments, including argon plasma coagulation, hyperbaric oxygen therapy, and supportive medical management, have variable efficacy, limited availability, and may be associated with substantial cost or procedure-related risks.

Sodium copper chlorophyllin (CHL) is a semi-synthetic chlorophyll derivative that activates the Nrf2 pathway and has demonstrated antioxidant, anti-inflammatory, and radioprotective properties in preclinical studies. Early-phase clinical studies have shown a favorable safety profile and encouraging efficacy in radiation-induced toxicities, including hemorrhagic cystitis, supporting further evaluation in radiation-induced GI bleeding.

This is a multicenter, randomized, double-blind, placebo-controlled Phase III superiority trial. Approximately 200 participants with late radiation-induced luminal GI bleeding will be randomized in a 1:1 ratio to receive either oral CHL 500 mg once daily or matching placebo for 3 months, in addition to standard medical management. Participants will be followed for up to 2 years after randomization.

The primary endpoint is the occurrence of grade 2 or higher anemia attributable to radiation-induced GI bleeding at 6 months. Secondary endpoints include changes in bleeding severity, gastrointestinal symptoms, endoscopic response, occult blood test conversion, anemia-related laboratory parameters, blood transfusion requirements, quality of life, safety, breakthrough bleeding, rescue therapy requirements, and cost-effectiveness.

The study is designed to determine whether CHL can provide an effective, safe, and affordable treatment option for patients with chronic radiation-induced GI bleeding while reducing anemia, transfusion requirements, and healthcare costs and improving patient quality of life.

• Chlorophyllin, Sodium Copper Complex (Drug): Sodium copper chlorophyllin 500 mg oral tablet administered once daily for 3 months in addition to standard medical management for late radiation-induced gastrointestinal bleeding. Participants are randomized to receive either chlorophyllin or a matching placebo in a double-blind manner.
• Placebo (Drug): A matching placebo tablet identical in appearance, packaging, and administration schedule to the chlorophyllin tablet. Participants will receive one placebo tablet orally once daily for 3 months in addition to standard medical management. The placebo is designed to maintain blinding in this double-blind, randomized trial.

Primary outcomes

• Grade 2 or higher anemia (CTCAE anemia version 5) due to uncontrolled bleeding [Up to 6 months after randomization]: Grade 2 or higher anemia (CTCAE anemia version 5) due to uncontrolled bleeding defines failure of intervention. This will be actively evaluated at 1,3 and 6 months and for the intervention to be successful, Hb should be >/=10gm/dl (at the same lab, where baseline Hb was evaluated) at 6 months from randomization. Interim Hb levels for unplanned patients visits and 1, 3 months will also be counted, where if Hb <8gm/gl, then the intervention will be deemed unsuccessful without waiting for 6 months and patient will be managed as per institutional protocol. Patients may still be followed up for recording institutional practice (interventions) and outcomes till 2 years follow up is completed.

Secondary outcomes

• CB-Score (chronic bleeding score) [2 Years]: Additionally, patients may be assessed with exploratory study specific objective + subjective criteria's at each visits as below: Assessment Item Pre - post effectiveness definition per item 1. Amount of bleeding Example: Small streak/ few drops /clots and fresh blood/copious amount in more than 50% episodes. Mandatory improvement of amount and percentage bleeding episodes per day in last one week. 2. Frequency of bleeding Daily/alt day/ weekly once /occasionally: once in two weeks or less. Mandatory improvement in frequency estimated in last one week. 3. Associated symptoms (pain/tenusmus/other) with CTCAE grade Optional improvement in CTCEA grade. 4. CTCAE grade Bleeding Should not deteriorate (intervention should be started only after stabilizing HB above 10 g/dl) 5. CTCAE grade Anemia Should not deteriorate (intervention should be started only after stabilizing HB above 10 g/dl) 6. Surgical Intervention Must not have been required (needed)
• Occult Blood Test Conversion Rate [2 Years]: Patients identified to be occult blood positive in stool at randomization and their conversion to test negative at Visit 2-6, may be estimated as a surrogate for subclinical mucosal healing shadowing clinical response. These may further be correlated with clinical response, QoL scores and endoscopic response assessment.
• Symptom Relief in Associated GI Symptom Complex [2 Years]: To assess improvements in related gastrointestinal symptoms such as pain, urgency, frequency, tenesmus, diarrhea and other additional associated late toxicity symptoms, PROMs following treatment and their inter-correlations.
• Endoscopic Response [2 Years]: To document and quantify endoscopic mucosal healing or improvement using RTOG grading where, Grade 0: No change or just congested mucosa, Grade 1: Minor changes, such as microulceration or mild telangiectasia (small, dilated blood vessels), Grade 2: Superficial ulceration (>1cm2) or significant telangiectasia, Grade 3: Deep ulceration, severe congestion, or marked bleeding and Grade 4: Necrosis, fistula, or perforation This is derived from OMED scoring coorelated with RTOG/EORTC morbidity scoring
• Anemia profile [2 Years]: It includes iron studies (serum iron, ferritin, total iron-binding capacity \[TIBC\], transferrin), serum vitamin B12, and serum folate levels. The nutritional background at baseline may be captured, and its improvement with treatment and supplementation may be charted and reported.
• Cost of Therapy [2 Years]: To evaluate the overall cost-effectiveness of CHL, including medication, monitoring, and adverse event management costs. The direct cost of various medicines/transfusions/admissions/procedures related to Late GI bleeding and its complications incurred by patients will be collated from electronic charts of patients and estimated to be compared. Cost effectiveness will also be estimated and compared using EQ-5D-5L questionnaire. This measures health in five domains namely mobility, self-care, usual activities, pain/discomfort and anxiety/depression. These responses are converted to a single index score (utility) which are then multiplied by time spent in that state to estimate the QALY. The exploratory analysis of estimating recovering quality of life utility index and incremental cost effectiveness ratio may be defined and estimated with available data.
• Transfusion Rates [2 Years]: To monitor and compare the number and frequency of blood transfusions required post-treatment between study arms during both parts.
• Quality of Life (QoL) QLQ-C30 [2 Years]: To assess health-related quality of life using validated patient-reported outcome measures, QLQ C30 Questionnaires at baseline and at every Visits ( 2-6 month) (+/- 1 month). Patient-reported outcomes will be analysed after obtaining the responses. EORTC questionnaires are available in Hindi, Marathi and Bangla languages. They will be provided to the literate patient in the language of their choice by the study coordinator for filling. In case of any difficulty in understanding any word or sentence, it would be explained by the study team. In the case of illiterate patients, patient relatives will be allowed to fill the form on the patient's behalf based on the patient's responses to the questions. The forms will be filled during the waiting period in OPD or for other investigations. Other scores are available only in English and will be filled by the patient directly if the patient or relatives know how to read and write English, or else
• Quality of Life (QoL) QLQ-PRT-20 [2 Years]: To assess health-related quality of life using validated patient-reported outcome measures EORTC questionnaire PRT-20 at baseline, one month on treatment (+/-1 week), 3 months (completion of study intervention; +/-2 weeks), and 6 months (+/- 1month), and then 6 monthly till two years (+/- 1 month).
• Questionnaire LENT-SOMA [2 Years]: To assess health-related quality of life using validated patient-reported outcome measures questionnaire LENT-SOMA at baseline, one month on treatment (+/-1 week), 3 months (completion of study intervention; +/-2 weeks), and 6 months (+/- 1month), and then 6 monthly till two years (+/- 1 month).
• Questionnaire EQ-5D-5L [2 Years]: To assess health-related quality of life using validated patient-reported outcome measures questionnaire EQ-5D-5L at baseline, one month on treatment (+/-1 week), 3 months (completion of study intervention; +/-2 weeks), and 6 months (+/- 1month), and then 6 monthly till two years (+/- 1 month).
• Breakthrough Bleeding [2 Years]: To evaluate the frequency of breakthrough or recurrent GI bleeding episodes.
• Rescue Therapy Requirements [2 Years]: To evaluate the need for re-initiation of Nrf2 therapy or alternative adjunctive treatments such as CHL.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age greater than 18 years.
2. Histologically confirmed malignancy who have previously received radiotherapy to the pelvis, abdomen, or mediastinum and subsequently developed late radiation-induced luminal gastrointestinal bleeding at least 6 months after completion of radiotherapy.
3. Currently no evidence of distant metastases or local recurrence associated with GI bleed, documented and proven as appropriate with the primary diagnosis.
4. Site of GI bleed localised by either CT angiography or endscopy (Vienna score) or as per best standards applicable in institutional practice and primary diagnosis.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
6. Ability to understand, voluntarily consent, and sign a written informed consent form prior to study participation.
7. Additional local symptoms associated with site of bleeding along with bleeding are allowed.
8. HB maintained >10 g/dl with or without transfusion before initiation of study intervention. Occult stool may be positive.
9. Previous bleed treatment failure (any, including HBOT/APC), or partial response to APC/HBOT or other treatment is allowed.
10. Patient reliable for follow-up for 2 years

Exclusion Criteria:

1. Diagnosed of ulcerative colitis or other histologically confirmed inflammatory bowel disease (IBD), disease such as ITP, TTP etc where patient may have bleeding tendencies which may be associated with GI bleed independently.
2. Presence of any other significant medical or psychiatric condition that, in the opinion of the investigator, may compromise the patient's safety, interfere with study participation or compliance, or confound interpretation of study results.
3. Poor anticipated compliance or follow-up reliability, as assessed by the investigator.
4. Failure to meet one or more inclusion criteria, rendering the patient ineligible for study participation.
5. Prophylactic use of Ecosprin, heparin, warfarin for certain medical conditions may be allowed.

• Prof. Rahul Krishnatry, Principal investigator, Tata Memorial Hospital