Monitoring, Immunologic
Conditions
Keywords
Colorectal Cancer, Chemotherapy, Rehabilitation, Mitochondria, Sodium Nucleinate
Brief summary
The goal of this clinical trial is to learn if adding sodium nucleinate to FOLFOX chemotherapy helps people with metastatic colorectal cancer (colon or rectal cancer that has spread). Researchers will also look at side effects and how people feel during treatment. The main questions this study aims to answer are: 1. Does adding sodium nucleinate help treatment work better? 2. Does it improve quality of life (how people feel and function day to day)? 3. Does it affect survival at one year? Researchers will compare: 1. FOLFOX chemotherapy plus sodium nucleinate versus 2. FOLFOX chemotherapy alone Participants will: 1. Be randomly assigned (like flipping a coin) to one of the two groups; 2. Receive four cycles of FOLFOX chemotherapy; 3. Take sodium nucleinate daily if assigned to that group; 4. Have checkups and blood tests during the study (including tumor marker blood tests such as CEA and CA 19-9); 5. Complete quality-of-life questionnaires and have other planned tests that look at immune cells and how certain blood cells work; 6. Be followed after treatment to see how they are doing, including up to one year after starting the study.
Detailed description
This randomized, single-blinded, parallel-group clinical trial was approved by the Local Ethics Committee of Kazakh National Medical University and conducted at oncology centers affiliated with university clinics in four regions of Kazakhstan. Participants had histologically confirmed metastatic colorectal cancer (T3-4 N1-2 M1). A total of 200 individuals were screened; 187 were enrolled and randomized. Participants were allocated in a 1:1 ratio using sealed envelopes to receive either (1) FOLFOX chemotherapy plus sodium nucleinate or (2) FOLFOX chemotherapy alone. The intervention group received sodium nucleinate 50 mg per day (25 mg in the morning and 25 mg at lunch), starting 1 week before the first chemotherapy cycle and continued daily for 4 months. Both groups received four cycles of FOLFOX per institutional protocols. Assessments included monthly clinical evaluation with general and biochemical blood tests during treatment. The following were assessed at baseline and at 1 month after completion of chemotherapy (approximately 5 months after baseline): FDG PET/CT, serum tumor markers (CEA and CA 19-9), peripheral blood immunologic status (CD4+/CD8+ ratio), and neutrophil mitochondrial activity (percentage of neutrophils with preserved mitochondrial function among 200 counted neutrophils). Baseline transthoracic echocardiography was performed to determine left ventricular ejection fraction. Health-related quality of life was assessed using the EORTC QLQ-C30 at baseline, post-treatment, and 1 year post-baseline. Analyses were performed using Statistica 7.0 (StatSoft, USA). Continuous outcomes were compared between groups using the Mann-Whitney U test as specified in the protocol.
Interventions
DIETARY_SUPPLEMENTAdenorine
Sodium nucleinate (Adenorine) is an immunomodulatory oligonucleotide preparation. In this trial, it was administered orally at 50 mg per day (25 mg in the morning and 25 mg at lunch before meals) for four months, starting 7 days before the first cycle of FOLFOX chemotherapy.
OTHERPlacebo
Matching placebo administered orally (25 mg morning, 25 mg lunch) for four months, identical in appearance, taste, and packaging to sodium nucleinate. Contains microcrystalline cellulose.
DRUGFOLFOX regimen
(Day 1-2: Oxaliplatin 100 mg/m2 IV infusion, given as a 120 minutes IV infusion in 500 mL D5W, concurrent with leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2) IV infusion, followed by 5-FU 400 mg/m2 IV bolus, followed by 46-hour 5-FU infusion (2400 mg/m2 for first two cycles, and may be increased to 3000 mg/m2 if tolerated by patient (no toxicity \> grade 1 during the first two cycles), days 3-14: Rest days)
Sponsors
MIPO Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Randomization 1:1 using computer-generated block randomization with variable block sizes, stratified by ECOG status, metastatic sites, and prior adjuvant chemotherapy. Allocation concealment: sequentially numbered, opaque, sealed envelopes (SNOSE); randomization table not disclosed to researchers. Blinded outcome assessors: intake nurse, lab technician, researcher performing measurements, social worker processing QoL questionnaires, and statistician (Group A/B until database lock). Treating clinicians were not blinded. All chemotherapy dose modifications (delays, reductions, cancellations) were governed by protocol-defined objective criteria (e.g., ANC \<1000/mm³, platelets \<50,000/mm³, CTCAE grade ≥3) with no investigator discretion. A blinded Endpoint Adjudication Committee reviewed 100% of modifications to verify adherence to objective criteria. Treating physician had no access to functional blood tests or QoL results during treatment; outcomes entered after treatment course compl
Intervention model description
The primary purpose of this treatment trial is to determine whether adding sodium nucleinate mitochondrial immunotherapy to FOLFOX chemotherapy improves quality of life and reduces one-year mortality in metastatic colorectal cancer.
Eligibility
Sex/Gender
ALL
Age
40 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed colorectal cancer. 2. Locally advanced or metastatic disease as treated with palliative FOLFOX per protocol (including metastatic disease \[M1\]). 3. Able to receive FOLFOX chemotherapy and to comply with study procedures. 4. Provided written informed consent.
Exclusion criteria
1. Active pulmonary tuberculosis. 2. Decompensated diabetes mellitus. 3. Decompensated cardiac, vascular, pulmonary, hepatic, or renal failure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Dose Intensity of FOLFOX | 1-4 cycles of FOLFOX | Relative Dose Intensity (RDI) over cycles 1-4 of FOLFOX, calculated as (delivered dose intensity / planned dose intensity) × 100. Dose intensity accounts for both dose reductions and treatment delays for oxaliplatin (mg/m²/week) and infusional 5-fluorouracil (mg/m²/week). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mitochondrial Activity of Neutrophils | Baseline (before start of chemotherapy) and post-treatment assessment 1 month after completion of chemotherapy | Mitochondrial activity of neutrophils assessed in peripheral blood as the percentage (%) of neutrophils with preserved mitochondrial function among 200 counted neutrophils per participant. Range 0-100%. Higher percentages indicate better preserved neutrophil mitochondrial function. Primary metric: change from baseline to 1 month after completion of chemotherapy. |
| Positron Emission Tomography/Computed Tomography (PET/CT) Tumour Metabolic Activity | Baseline (before start of chemotherapy) and follow-up FDG-PET/CT 1 month after completion of chemotherapy (approximately 5 months after baseline). | Metabolic response to treatment assessed by \[18F\]FDG PET/CT using EORTC PET response criteria based on the change in tumor FDG uptake (e.g., SUV metric) between baseline and follow-up. Participants were classified into mutually exclusive categories: partial metabolic response (PMR) (≥25% decrease in tumor FDG uptake), stable metabolic disease (SMD) (does not meet PMR or PMD), or progressive metabolic disease (PMD) (≥25% increase in tumor FDG uptake and/or new FDG-avid lesions). Higher metabolic activity and PMD indicate worse disease activity. |
| CEA Response (≥50% Decrease From Baseline) | Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline) | Serum CEA concentration measured in peripheral blood and reported in ng/mL. Higher CEA values generally indicate higher tumor burden and are used to monitor treatment response in conjunction with imaging. CEA response defined as a ≥50% decrease in serum CEA concentration from baseline to 1 month after completion of chemotherapy. |
| EORTC QLQ-C30 Global Health Status/QoL (GHS/QoL) | Baseline (before start of chemotherapy); 1 month after completion of 4 cycles (approximately 5 months after baseline); 1 year post-baseline | Global health status/quality of life subscale from the EORTC QLQ-C30. Scores are linearly transformed to a 0-100 scale. Higher scores indicate better global health status/quality of life (better outcome). Minimum = 0, maximum = 100. This is a subscale score, not a total scale score. |
| CD4+/CD8+ T-Cell Ratio (Peripheral Blood) | Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline) | CD4+/CD8+ T-cell ratio measured in peripheral blood (unitless ratio). The prespecified metric is the change in CD4+/CD8+ ratio from baseline to 1 month after completion of chemotherapy. |
| Left Ventricular Ejection Fraction (LVEF) by Echocardiography | baseline (before start of chemotherapy) | Left ventricular ejection fraction (LVEF) ≥50% by echocardiography at baseline was required for study inclusion. Patients with LVEF \<50% were excluded. |
| CA 19-9(Carbohydrate Antigen 19-9) Response (≥50% Decrease From Baseline) | Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline) | CA 19-9 response defined as a ≥50% decrease in serum CA 19-9 concentration from baseline to 1 month after completion of chemotherapy. CA 19-9 measured in U/mL. Higher CA 19-9 values indicate higher tumor burden (worse outcome). Normal range approximately 0-27 U/mL. |
Countries
Kazakhstan
Participant flow
Recruitment details
Patients with histologically confirmed metastatic colorectal cancer (stage M1 only) were recruited at oncology centers affiliated with university clinics in 4 regions of Kazakhstan. Active enrollment began on July 15, 2022 and was completed in July 2024.
Pre-assignment details
Of 200 patients screened, 187 met eligibility criteria, provided informed consent, and were enrolled (randomized). Thirteen patients were screening failures: 8 did not meet inclusion/exclusion criteria, 5 withdrew consent before randomization.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 10.2 |
| Primary tumour site (colon vs rectum) Colon | 45 Participants |
| Primary tumour site (colon vs rectum) Rectum | 53 Participants |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment Kazakhstan | 187 Participants |
| Sex: Female, Male Female | 43 Participants |
| Sex: Female, Male Male | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 89 | 27 / 98 |
| other Total, other adverse events | 6 / 89 | 52 / 98 |
| serious Total, serious adverse events | 13 / 89 | 52 / 98 |
Outcome results
None listed