THE EFFECT OF LUMBRICUS RUBELLUS DLBS1033 EXTRACT IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

THE EFFECT OF LUMBRICUS RUBELLUS DLBS1033 EXTRACT ON LEVELS OF HIGH-SENSITIVITY C-REACTIVE PROTEIN, VASCULAR ENDOTHELIAL GROWTH FACTOR, AND QUALITY OF LIFE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

This randomized, open-label, controlled trial aims to evaluate the effect of oral Lumbricus Rubellus extract DLBS1033 as adjunctive therapy on inflammatory biomarker (hs-CRP), angiogenic factor (VEGF), and quality of life in patients with Type 2 Diabetes Mellitus. Sixty eligible patients attending the Endocrinology Outpatient Clinic of RSUD Dr. Moewardi Surakarta will be randomized into three groups: two intervention groups receiving standard DM therapy combined with DLBS1033 (490 mg t.i.d. as either 3×1 tablet or 3×2 tablets daily) and one control group receiving standard DM therapy alone, over a 4-week observation period from May to June 2026. Primary outcomes include changes in serum hs-CRP and VEGF levels; secondary outcome is health-related quality of life assessed by EQ-5D-5L.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Oral Lumbricus Rubellus DLBS1033 (Low Dose); Other: Standard Diabetes Mellitus Therapy; Drug: Oral Lumbricus Rubellus DLBS1033 (High Dose)

Detailed Description

Type 2 Diabetes Mellitus (T2DM) is a major global health problem characterized by chronic hyperglycemia, persistent low-grade systemic inflammation, and vascular endothelial dysfunction. These pathological processes are central to the development of micro- and macrovascular complications, which are the leading causes of morbidity, mortality, and reduced quality of life in patients with T2DM.

Chronic hyperglycemia activates multiple pathophysiological pathways, including mitochondrial oxidative stress, the Advanced Glycation End Products (AGEs)-RAGE signaling axis, and impaired insulin signaling, collectively creating sustained systemic microinflammation and progressive endothelial damage. This endothelial dysfunction underlies the development of atherosclerosis, microcirculatory impairment, and pathological angiogenesis in T2DM patients.

High-sensitivity C-Reactive Protein (hs-CRP), a sensitive marker of systemic inflammation, is significantly elevated in T2DM and correlates with increased cardiovascular complication risk. Concurrently, Vascular Endothelial Growth Factor (VEGF), the primary mediator of endothelial cell proliferation and survival, exhibits the so-called 'VEGF paradox' in T2DM, whereby systemically elevated VEGF fails to produce functional neovascularization and instead promotes dysangiogenesis and pathological vascular permeability. These two pathways-hs-CRP-mediated inflammation and VEGF-mediated angiogenesis-interact in a mutually reinforcing pathological cycle that accelerates vascular complication progression.

Current T2DM management primarily targets glycemic control, which, while effective in reducing long-term complications, is insufficient to fully suppress chronic inflammation and correct vascular dysfunction. Adjuvant therapeutic strategies targeting non-glycemic pathogenic pathways, particularly inflammation and endothelial dysfunction, are therefore needed.

Lumbricus Rubellus extract (DLBS1033), produced by PT Dexa Medica through the Dexa Laboratories of Biomolecular Sciences (DLBS) in compliance with Good Manufacturing Practice (GMP) standards, contains low molecular weight proteins (Lumbricus Low Molecular Weight Proteins/LLP), including lumbrokinase-a serine protease enzyme with fibrinolytic, antithrombotic, and anti-inflammatory activities. Previous studies have demonstrated that lumbrokinase can suppress inflammatory mediators such as TNF-α and NF-κB, inhibit platelet aggregation, degrade fibrinogen, and improve microcirculatory function. However, its simultaneous effects on both hs-CRP and VEGF in T2DM patients remain insufficiently studied.

Eligible patients with T2DM attending the Endocrinology Outpatient Clinic of RSUD Dr. Moewardi Surakarta will be recruited consecutively and randomized using a block randomization method (fixed block size of 4) into three parallel groups: Intervention Group A (standard DM therapy + DLBS1033 490 mg t.i.d. as 3×1 tablet daily for 4 weeks), Intervention Group B (standard DM therapy + DLBS1033 490 mg t.i.d. as 3×2 tablets daily for 4 weeks), and Control Group (standard DM therapy alone). Randomization sequences will be generated independently using web-based software (www.random.org) and secured to maintain allocation concealment.

At baseline, all subjects will undergo clinical and demographic data collection, physical examination, and venous blood sampling for complete blood count, HbA1C, creatinine, SGOT, SGPT, hs-CRP (by immunoturbidimetric method), and VEGF (by Enzyme-Linked Immunosorbent Assay/ELISA). During the 4-week intervention period, biweekly follow-up visits will assess therapy adherence using the Medication Adherence Report Scale (MARS) and monitor for adverse effects. At week 4, repeat measurements of hs-CRP, VEGF, creatinine, SGOT, SGPT, MARS score, and health-related quality of life using the EQ-5D-5L questionnaire will be performed. Statistical analysis will use One-Way ANOVA (normally distributed data) or Kruskal-Wallis test (non-normally distributed data), with Analysis of Covariance (ANCOVA) and constrained Longitudinal Data Analysis (cLDA) for sensitivity analyses controlling for confounders including age, sex, nutritional status, comorbidities, and baseline biomarker values.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Indonesia
  • Central Java
    • Surakarta, Central Java, Indonesia, 57126
      • Dr. Moewardi Regional General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients diagnosed with Type 2 Diabetes Mellitus currently on therapy.
• Patients receiving Lumbricus Rubellus extract therapy during outpatient care at the Endocrinology Clinic.
• Adults aged >18 years, both male and female.
• Willing to undergo monthly evaluations during the 1-month study period

Exclusion Criteria:

• Patients with diabetic foot ulcer grade 1-2.
• Patients with Diabetic Kidney Disease (DKD) Stage 5.
• Patients with chronic liver disease.
• Post-operative patients.
• Patients with malignancy.
• Patients with autoimmune disease or active infection.
• Non-compliant or uncooperative patients during the monitoring period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (Low Dose); Patients with Type 2 Diabetes Mellitus who received oral Lumbricus Rubellus extract DLBS1033 (490 mg, DISOLF film-coated tablet, Dexa Medica, 3×1 tablet daily) combined with standard DM therapy during the 4-week observation period.	Drug: Oral Lumbricus Rubellus DLBS1033 (Low Dose); DLBS1033: 490 mg, DISOLF film-coated tablet, Dexa Medica, 3×1 tablet t.i.d. for 4 weeks; Other: Standard Diabetes Mellitus Therapy; Standard Diabetes Mellitus Therapy
Experimental: Group B (High Dose); Patients with Type 2 Diabetes Mellitus who received oral Lumbricus Rubellus extract DLBS1033 (490 mg, DISOLF film-coated tablet, Dexa Medica, 3×2 tablets daily) combined with standard DM therapy during the 4-week observation period.	Other: Standard Diabetes Mellitus Therapy; Standard Diabetes Mellitus Therapy; Drug: Oral Lumbricus Rubellus DLBS1033 (High Dose); DLBS1033: 490 mg, DISOLF film-coated tablet, Dexa Medica, 3×2 tablets t.i.d. for 4 weeks
Placebo Comparator: Control Group; Patients with Type 2 Diabetes Mellitus who received standard DM therapy alone during the 4-week observation period.	Other: Standard Diabetes Mellitus Therapy; Standard Diabetes Mellitus Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hs-CRP (High-sensitivity C-Reactive Protein)	Serum hs-CRP levels measured using immunoturbidimetric method at baseline and at week 4 post-initiation of therapy, to assess the effect of DLBS1033 on systemic inflammatory status in Type 2 Diabetes Mellitus patients.	Baseline and week 4
VEGF (Vascular Endothelial Growth Factor)	Serum VEGF levels measured using Enzyme-Linked Immunosorbent Assay (ELISA) at baseline and at week 4 post-initiation of therapy, to assess the effect of DLBS1033 on angiogenic factor regulation in Type 2 Diabetes Mellitus patients.	Baseline and week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life - EQ-5D-5L	Assessment of health-related quality of life using the EQ-5D-5L (EuroQol 5 Dimensions 5 Levels) instrument, comprising a five-dimension descriptive system (mobility, self-care, usual activities, pain/discomfort, anxiety/depression, each rated 1-5) and the EQ Visual Analogue Scale (EQ-VAS, 0-100). Assessment performed at baseline and at week 4. Higher EQ-VAS scores and lower dimension levels indicate better health-related quality of life.	Baseline and week 4

Collaborators and Investigators

• Sponsor: Universitas Sebelas Maret
• Investigators: Principal Investigator: Nabila Aushaf Prasetyo, MD, Department of Internal Medicine, Faculty of Medicine, Universitas Sebelas Maret Surakarta

Publications and helpful links

General Publications

• Dewi NWS, Mahendra AN. The in-vivo anti-inflammatory effect of red earthworm (Lumbricus Rubellus) ethanolic extract from organic farmland in Bali, Indonesia. Bali Med J 2020;9(3):652-655
• Öz S, Özden H, Yıldız F, et al. Protective effect of Lumbricus Rubellus Hoffmeister extract in experimental renal ischemia/reperfusion injury in the nephrectomy rats. INDIAN J Exp Biol 2023;61(December)
• Semih Oz, Yildiz F, Senturk H, et al. Protective Effects of Lumbricus Extract on the Antioxidant System and Liver in an Experimentally Created Liver Ischemia Reperfusion Injury Model in Rats. Biol Bull 2023;50(3):276-283

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2026
• Primary Completion (Actual): June 21, 2026
• Study Completion (Actual): June 28, 2026

Study Registration Dates

• First Submitted: June 28, 2026
• First Submitted That Met QC Criteria: June 28, 2026
• First Posted (Actual): July 6, 2026

Study Record Updates

• Last Update Posted (Actual): July 6, 2026
• Last Update Submitted That Met QC Criteria: June 28, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Quality of Life; C-Reactive Protein; Diabetes Mellitus Type 2; Vascular Endothelial Growth Factor; DLBS1033; EQ-5D-5L; High-Sensitivity; Oral Lumbrokinase
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2
• Other Study ID Numbers: DLBS1033 on Diabetes Mellitus

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: June 28th, 2026-June 28th, 2027
• IPD Sharing Access Criteria: Open access, every journal visitor
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No