The Effect of Oral DLBS1033 in Patients With Diabetic Polyneuropathy

The Effect of Oral DLBS1033 as Adjuvant Therapy on Inflammatory Biomarkers, Neuroregeneration Biomarkers, and Disease Severity in Patients With Diabetic Polyneuropathy: A Randomized Controlled Trial (An Evaluation of Changes in TCNS, TNF-α, NGF, and Sensory Nerve Conduction Study of the Sural Nerve)

This study aims to evaluate whether oral DLBS1033 can improve clinical symptoms and biological markers of nerve damage in adults with diabetic polyneuropathy. The trial enrolls patients with type 2 diabetes who show clinical signs of peripheral nerve injury.

Participants will receive either DLBS1033 as adjuvant therapy or standard therapy alone for 28 days. The study will compare changes in neuropathy severity (Toronto Clinical Neuropathy Score), inflammatory biomarkers (TNF-α), neuroregeneration biomarkers (Nerve Growth Factor), and sensory nerve conduction parameters of the sural nerve between the two groups. Blood tests, clinical assessments, and nerve conduction studies will be performed at baseline and follow-up visits. Participants will also report any symptoms or adverse events throughout the study.

This study is a double-blind, randomized, placebo-controlled clinical trial conducted at RSUD Dr. Moewardi, Surakarta. Participants are adults aged 40-60 years with clinically diagnosed diabetic polyneuropathy and HbA1c levels between 7-10%. After screening and confirmation of eligibility, participants are randomized in a 1:1 ratio to receive either oral DLBS1033 (3 × 980 mg daily for 28 days) or placebo, in addition to standard DPN management. Randomization is performed by a third party using permuted block randomization via an online allocation system.

The study evaluates changes in:

• Inflammatory activity, measured by serum TNF-α
• Neuroregeneration, measured by serum NGF
• Clinical severity, assessed using the Toronto Clinical Neuropathy Score (TCNS)
• Electrophysiological function, assessed by sensory nerve conduction velocity and amplitude of the sural nerve These parameters are measured at baseline (Day 0) and after 28 days of treatment. A ±2-day window (Day 26-30) is permitted for follow-up assessments. Participants continue receiving their assigned intervention during this window.

Rationale DPN is driven by multiple interacting mechanisms, including oxidative stress, microvascular ischemia, and chronic low-grade inflammation. TNF-α is a key pro-inflammatory cytokine implicated in nerve injury, demyelination, and axonal degeneration. Elevated TNF-α levels correlate with DPN severity and may serve as a therapeutic target. Conversely, NGF is essential for the survival and regeneration of small-fiber and large-fiber neurons. Reduced NGF availability contributes to impaired nerve repair and progression of neuropathy. The protocol highlights that "NGF levels are significantly reduced in patients with diabetic neuropathy," and that restoring NGF may support nerve recovery.

DLBS1033 has demonstrated the ability to reduce TNF-α expression and enhance NGF production in preclinical models. It also improves microcirculation through fibrinolytic and antiplatelet effects, which may alleviate endoneurial ischemia-a major contributor to DPN. These combined mechanisms provide a strong biological rationale for evaluating DLBS1033 as an adjuvant therapy.

Study Procedures

Participants undergo the following procedures:

• Informed consent and baseline evaluation, including medical history, physical examination, TCNS scoring, and laboratory tests (HbA1c, creatinine, SGOT/SGPT).
• Electrophysiological testing using standard EMG-NCS equipment to measure sural nerve conduction velocity and SNAP amplitude.
• Blood sampling for TNF-α, NGF, fasting glucose, post-prandial glucose, and lipid profile.
• Administration of study medication (DLBS1033 or placebo) for 28 days.
• Follow-up assessments on Day 28 (or within the ±2-day window), repeating all baseline evaluations.
• Monitoring for adverse events, with documentation of any participant complaints throughout the study.

These procedures are described in the protocol: "Peneliti melakukan anamnesis dan pemeriksaan fisik… serta ENMG… pada hari pertama… [and] pada hari ke-28… Selama periode tersebut, pasien tetap menerima terapi adjuvan oral DLBS1033."

Data Quality and Management

• Although this study is not a patient registry, the protocol incorporates several quality assurance measures consistent with ClinicalTrials.gov expectations:
• Standardized data collection using case report forms for all clinical, laboratory, and electrophysiological data.
• Laboratory testing performed using validated equipment (e.g., ELISA kits for TNF-α and NGF, HPLC for HbA1c, Beckman Coulter analyzers for chemistry panels).
• Blinding of participants and investigators to treatment allocation to minimize bias.
• Randomization integrity ensured through third-party allocation and concealed assignment.
• Data verification through completeness checks, coding, and tabulation before analysis.
• Handling of missing data through predefined window periods and statistical adjustment.
• Statistical analysis plan using ANCOVA and difference-in-differences (DiD) to compare changes between groups while adjusting for baseline covariates.

The protocol states: "Data yang terkumpul… dilakukan pemeriksaan kelengkapan… diberi kode… dilakukan tabulasi… Perbandingan efek kelompok perlakuan dan kontrol dilakukan menggunakan ANCOVA… Pendekatan difference-in-differences digunakan…"

Expected Contribution

This study is the first randomized controlled trial to evaluate DLBS1033 as an adjuvant therapy for diabetic polyneuropathy. By integrating clinical scoring, electrophysiological testing, and biomarker analysis, it aims to provide comprehensive evidence on whether DLBS1033 can:

• Reduce inflammation
• Enhance neuroregeneration
• Improve nerve conduction
• Reduce clinical severity of neuropathy

Given the high prevalence of DPN and the limited availability of disease-modifying treatments, the findings may support the development of new therapeutic strategies and inform future larger-scale trials.

Inclusion Criteria:

• Adults aged 40-60 years diagnosed with diabetic polyneuropathy by a neurologist or neurology resident.
• Patients with HbA1c levels between 7-10% within the past 30 days.
• Willing to participate and able to sign the informed consent form.

Exclusion Criteria:

• Pregnant, breastfeeding, or planning pregnancy.
• History of other neurological diseases such as stroke, myelopathy, alcoholic neuropathy, or compressive radiculopathy.
• Significant renal impairment (creatinine > 1.5× upper limit of normal), hepatic impairment (SGOT or SGPT > 3× upper limit of normal), or severe cardiac disease (NYHA class III-IV heart failure).
• History of alcohol consumption for ≥ 5 consecutive years.
• Heavy smoker (Brinkman Index > 600).
• Known allergy or intolerance to DLBS1033.
• Autoimmune disease, malignancy, or acute and/or chronic inflammatory conditions other than diabetic polyneuropathy.
• Participation in another interventional pharmacological clinical study within 30 days prior to screening.
• Currently taking anti-inflammatory and/or antioxidant medications.