Comparing Oral Lumbrokinase DLBS1033 and Betahistine Mesylate in Benign Paroxysmal Positional Vertigo: A Randomized Comparative Study on Inflammatory Markers, Quality of Life, and Symptom Resolution
Phase: PHASE4
Conditions: Benign Paroxysmal Positional Vertigo (Disorder)
Sponsor: Universitas Sebelas Maret

COMPARING ORAL LUMBROKINASE DLBS1033 
AND BETAHISTINE MESYLATE IN BENIGN 
PAROXYSMAL POSITIONAL VERTIGO 
 
STUDY ID: 623/II/HREC/2024 
DOCUMENT DATE: APRIL 1ST, 2024 
 
STUDY PROTOCOL, STATISTICAL ANALYSIS PLAN (SAP),  
AND INFORMED CONSENT FORM (ICF) 
 
 
 
 
 
 
 
 
 
Researchers’ Names: 
1. Stefanus Erdana Putra, MD.  
2. Prof. Diah Kurnia Mirawati, MD., Ph.D.  
3. Ratih Puspita Febrinasari, MD., Ph.D.  
4. Subandi, MD., Ph.D. 
 
 
DEPARTMENT OF NEUROLOGY 
FACULTY OF MEDICINE UNIVERSITAS SEBELAS MARET 
SURAKARTA, CENTRAL JAVA, INDONESIA 
2024 

1. STUDY PROTOCOL 
 
1.1 Objectives  
The research aims to determine the differences in: 
• 
Decrease in IL-1β levels between benign paroxysmal positional vertigo (BPPV) patients 
receiving oral lumbrokinase DLBS1033 therapy and those receiving betahistine therapy. 
• 
Decrease in TNF-α levels between BPPV patients receiving oral lumbrokinase DLBS1033 
therapy and those receiving betahistine therapy. 
• 
Decrease in VCAM-1 levels between BPPV patients receiving oral lumbrokinase 
DLBS1033 therapy and those receiving betahistine therapy. 
• 
Quality of life between BPPV patients receiving oral lumbrokinase DLBS1033 therapy and 
those receiving betahistine therapy. 
• 
Time to improvement of dizziness symptoms between BPPV patients receiving oral 
lumbrokinase DLBS1033 therapy and those receiving betahistine therapy. 
 
1.2 Design and Methods 
• 
Type of research: This study is a clinical trial with a double-blind randomized controlled 
trial design. 
• 
Place and time of research: The study was conducted at the neurology polyclinic of Dr. 
Moewardi Regional General Hospital, Surakarta. Data collection began after obtaining 
ethics committee approval and continued until the required sample size was met, from April 
to August 2024. 
• 
Research population: The actual research population consists of patients at the neurology 
polyclinic of Dr. Moewardi Regional General Hospital, Surakarta, who met the inclusion 
and exclusion criteria. 
• 
Research subjects: Subject selection was carried out using purposive sampling. 
o Inclusion criteria: BPPV patients at the neurology polyclinic of Dr. Moewardi 
Regional General Hospital, aged 18-65 years, diagnosed by a neurologist or 
neurology polyclinic resident based on a history of worsening vertigo, nausea, 
vomiting, and imbalance with head movements, and findings of torsional 
nystagmus with latency, fatigability, and duration less than 60 seconds on Dix-

Hallpike maneuver; able to speak, read, and write Indonesian; and willing to 
cooperate as research subjects by signing the informed consent form. 
o Exclusion criteria: Pregnant and breastfeeding patients; patients with neurological 
deficits indicative of central vertigo based on anamnesis and physical examination; 
patients with a history of ear infection, hearing impairment, tinnitus, and head 
trauma; patients with thyroid disorders, diabetes mellitus, genu osteoarthritis, 
history of neoplasm, history of heart disease and hypertension, history of 
ear/mastoid surgery, and currently experiencing other inflammatory and infectious 
conditions; patients with cognitive impairment based on attention and memory 
examination; patients participating in other clinical studies within 30 days before 
screening. 
o Drop-out criteria: Patients who could not complete the entire research procedure; 
patients who did not follow procedures properly; patients who did not complete the 
DHI and VSS-SF questionnaires after receiving therapy. 
• 
Sample size: The minimum sample size was calculated using Sopiyudin's sample size1 
formula with a 95% confidence interval (CI) and 5% confidence limits. Based on a total 
population of 751 peripheral vertigo patients treated at the neurology polyclinic of Dr. 
Moewardi Hospital in the last year, the calculation resulted in a minimum sample of 40 
patients. An additional 10% was added to anticipate dropouts, making the total sample size 
44 patients. 
• 
Variable identification: 
o Independent variable: BPPV therapy. 
o Dependent variables: inflammation level, quality of life, time to improvement of 
dizziness symptoms in BPPV patients. 
o Confounding variables: age, body mass index, gender. 
• 
Operational definition of research variables: 
o BPPV therapy: Administration of oral lumbrokinase (DLBS 1033, 2x490 mg daily) 
or betahistine (2x12 mg daily) for 14 days to diagnosed BPPV patients. 
• 
Research instruments: Dizziness Handicap Inventory (DHI) and Vertigo Symptom Scale 
Short Form (VSS-SF) questionnaires, and biomarker examination (IL-1β, TNF-α, VCAM-
1) using Human Quantikine R&D Systems kits on a Thermo Fisher Invitrogen auto-
analyzer according to manufacturer specifications. 
• 
Randomization protocol: The study protocol involved a two-block randomization to ensure 
balanced group assignments. The random sequences for the group allocation were 
generated by independent personnel of the direct study management and kept in sealed 

envelopes. This allocation concealment ensured that neither the investigator team nor the 
participants knew their assigned treatment. Each package was coded with the subject 
identification number according to the generated random number and assigned to each 
eligible subject. These codes remained unrevealed until the study's completion.  
 
1.3 Relevant Scientific Background  
Over the past decade, researchers have explored new pathophysiological theories, proposing a 
connection between BPPV and oxidative stress, which triggers an inflammatory process 
explainable by ultrastructural mechanisms. Walther et al. demonstrated that human otoconia can 
exhibit varying degrees of ultrastructural degeneration, from minor to extensive changes.2 Severe 
morphological alterations can manifest as fractures with substantial loss of calcium-rich otoconial 
material. High-grade disintegration of otoconia leads to complete dissolution and fragmentation of 
calcium-rich material into the endolymph, potentially causing BPPV symptoms. Calcium 
metabolism and oxidative stress, intertwined processes, closely involve inflammation. The 
endoplasmic reticulum, a primary calcium storage organelle, can increase calcium influx under 
stress, triggering a cascade of reactive oxygen species (ROS) formation in mitochondria. 3 
Further supporting this, Güçlütürk et al. investigated the potential role of inflammation in BPPV 
by studying the levels of IL-1β, IL-6, and TNF-α.4 These pro-inflammatory mediators were 
significantly higher in BPPV patients and decreased with routine Brandt-Daroff repositioning 
maneuvers performed over 14 days. This suggests a possible inflammatory component in BPPV 
pathogenesis. Whether it is oxidative stress, otolith formation, migration into the semicircular 
canals, or the vertigo attacks in BPPV, a primary increase in inflammatory mediators can result. 
These novel findings, elucidating the crucial role of inflammation in BPPV pathophysiology, offer 
new avenues for pharmacological treatment. Conventional medications like betahistine or 
flunarizine, often prescribed for BPPV, primarily offer symptomatic relief without addressing the 
underlying cause. Furthermore, not all patients are amenable to routine maneuver therapy, such as 
the Brandt-Daroff maneuver, a definitive BPPV treatment proven to reduce pro-inflammatory 
mediators when performed consistently for 14 days.4 
In recent years, particularly since the COVID-19 pandemic, Traditional Indonesian Modern 
Medicines, or Obat Modern Asli Indonesia (OMAI)—natural and indigenous Indonesian drugs 
with scientific evidence of safety and efficacy—have seen rapid development.5 Among OMAI 
with potential for BPPV pharmacotherapy are Gingko biloba and oral lumbrokinase DLBS1033, 
which contains Lumbricus rubellus or earthworm extract. The oral lumbrokinase DLBS1033 
exhibits pleiotropic effects, effectively inhibiting the expression of inflammatory mediators 
implicated in BPPV pathophysiology, including NF-κβ, TNF-α, and VCAM-1.6 
 

1.4 Informed Consent  
The study includes a detailed Informed Consent form (attached in this document), which outlines 
essential information for prospective participants, including the research title, type, researchers' 
names and addresses, research location (Neurology Polyclinic and Clinical Pathology Laboratory 
of Dr. Moewardi Regional General Hospital Surakarta), study objectives, procedures (interviews, 
physical examination, blood sampling for biomarkers), participant selection criteria, voluntary 
participation, confidentiality, benefits (free blood sampling and biomarker analysis, access to 
results, transportation allowance of IDR 100,000 per visit for blood examination), and potential 
risks (pain at the blood sampling site). 
 
 

2. STATISTICAL ANALYSIS PLAN (SAP) 
 
2.1 Data Analysis  
Statistical analysis was performed using SPSS for Windows version 25.0. 
 
2.2 Specific Statistical Methods 
• 
Normality test: The Kolmogorov-Smirnov test was used to check the normality of the data 
distribution for all variables. The Kolmogorov-Smirnov test was performed to verify the 
assumption of normal distribution for all variables, confirming that the data met this critical 
assumption for the subsequent parametric tests. 
• 
Comparison between groups (day 7 and day 14): 
o Independent T-test: This test was used to determine significant differences between 
the oral lumbrokinase DLBS1033 group and the betahistine group for: 
▪ 
Mean DHI scores, 
▪ 
Mean VSS-SF scores, 
▪ 
Mean TNF-α levels, 
▪ 
Mean IL-1β levels, 
▪ 
Mean VCAM-1 levels. 
• 
Analysis of symptom improvement time (multiple repeated ANOVA): 
o Given the significant statistical differences found with the independent T-test, 
further analysis regarding the time to symptom improvement in BPPV patients 
receiving oral lumbrokinase DLBS1033 was performed using multiple repeated 
ANOVA.  
• 
Post-hoc analysis: Tukey B post-hoc test was used to compare the mean scores/levels 
between groups.  
 
 

3. INFORMED CONSENT FORM (ICF) 
 
Essential Information for Prospective Research Participants 
Field 
Details 
Research Title 
Comparing Oral Lumbrokinase DLBS1033 and Betahistine Mesylate in 
Benign Paroxysmal Positional Vertigo 
Research Type 
Clinical Trial 
Researchers' 
Names 
1. Stefanus Erdana Putra, MD.  
2. Prof. Diah Kurnia Mirawati, MD., Ph.D.  
3. Ratih Puspita Febrinasari, MD., Ph.D.  
4. Subandi, MD., Ph.D. 
Researchers' 
Address 
Dr. Moewardi Regional General Hospital, Kolonel Sutarto Street Number 
132, Jebres, Surakarta, Central Java, Indonesia, 57126 
Research 
Location 
Neurology Polyclinic and Clinical Pathology Laboratory, Dr. Moewardi 
Regional General Hospital, Surakarta 
 
RESEARCH INFORMATION SHEET 
Good morning/afternoon/evening, esteemed Participant, 
We are lecturers and neurology residents from the Faculty of Medicine, Universitas Sebelas Maret, 
currently conducting research at Dr. Moewardi Regional General Hospital, Surakarta. 
This research aims to determine the differences in inflammation levels, quality of life, and 
dizziness symptom improvement time in patients with Benign Paroxysmal Positional Vertigo 
(BPPV) who receive oral lumbrokinase DLBS1033 therapy compared to patients who receive 
betahistine therapy. This study will be conducted during your treatment as a BPPV patient at 
the Neurology Outpatient Clinic and Clinical Pathology Laboratory of Dr. Moewardi Regional 
General Hospital, Surakarta. 
The researchers will conduct a brief interview to gather information on your current and past 
medical history and a physical examination of the research participants. Furthermore, researchers 
will also collect blood samples from research participants for biomarker examination, which will 
be conducted at the Clinical Pathology Laboratory of Dr. Moewardi Regional General Hospital, 
Surakarta. 

You are invited to participate as a subject because you are a BPPV patient who meets the 
inclusion criteria for this study. Suppose you agree to participate in this research. In that case, 
you will be asked to sign and write your identity and the date on the confirmation consent form 
to participate as a research participant. 
If you decide not to participate, this will not affect your medical care. Your participation in this 
study is voluntary. You have the full right to withdraw or cancel your participation anytime. All 
information in this study is confidential. The subjects' identities will be anonymized and used 
solely for research and data processing. 
This research will be conducted during your visits or attendance at the hospital. By participating 
in this study, you can play an essential role in providing scientific evidence that assists clinicians 
in clinical decision-making regarding the application of oral lumbrokinase therapy as part of the 
causative therapy for BPPV patients. Thus, you indirectly help provide scientific knowledge to the 
public that can later be used in clinical decision-making. The results of this study are also expected 
to provide valuable information for advancing medical science and technology in Indonesia, 
especially in the field related to BPPV. The results of this study are novel in the medical field. 
You will be exempt from blood sample collection fees and biomarker analysis fees for each blood 
test. The test results can be communicated to you as a research subject. As a subject, you have 
the full right to access your data. In addition, you will receive transportation money of IDR 
100,000 (one hundred thousand rupiah) per visit for the examination each time you come for a 
blood test. 
As a subject in this study, you will be involved in venous blood collection. This procedure may 
cause pain at the blood collection site. In some cases, this process may also cause slight bruising 
or swelling. So far, venous blood collection has reported no serious side effects. If there is bruising 
or hematoma at the former blood collection site, the researchers and Dr. Moewardi Regional 
General Hospital will manage it according to applicable clinical practice guidelines. 
This research is a clinical trial. Post-blood collection management will be adjusted to the clinical 
practice guidelines at Dr. Moewardi Regional General Hospital. For patients, payment will be 
adjusted according to the payment/insurance scheme and patient care costs, and if other 
examinations are needed, all costs will be borne by the researchers. 
No additional interventions or treatments will be given to you as a respondent. There are no 
conflicts of interest. This research is self-funded and comes from the funds of the researchers and 
research team members. 
The research ethics committee has approved this research protocol. As a respondent, you can 
contact the Health Research Ethics Committee of Dr. Moewardi Regional General Hospital, 
Surakarta. The researchers will also submit a report to the Ethics Committee of Dr. Moewardi 
Regional General Hospital, Surakarta. 

If there is anything you do not understand, please feel free to ask us directly or contact us at 
(+62)85642134155 (Stefanus Erdana Putra) or (+62)271634634 (Health Research Ethics 
Committee of Dr. Moewardi Regional General Hospital). We thank you for your attention and 
assistance. 
 
Sincerely, 
1. Stefanus Erdana Putra, MD.  
2. Prof. Diah Kurnia Mirawati, MD., Ph.D.  
3. Ratih Puspita Febrinasari, MD., Ph.D.  
4. Subandi, MD., Ph.D. 
 

 
CONSENT FORM FOR PARTICIPATION IN RESEARCH 
I, the undersigned, hereby declare my willingness to participate in the research titled "Comparison 
of Inflammation Levels, Quality of Life, and Dizziness Symptom Improvement Time in Benign 
Paroxysmal Positional Vertigo Patients Receiving Oral Lumbrokinase DLBS 1033 Therapy vs. 
Betahistine (A Study on Changes in IL-1β, TNF-α, and VCAM-1 Levels)" at Dr. Moewardi 
Regional General Hospital, Surakarta. I have been informed that the researchers have obtained 
permission to conduct this research and that it will not harm me during the research procedures. 
Name  
 
: 
……………………………………………………………………………….  
Address 
 
: 
……………………………………………………………………………….  
Phone Number 
: 
………………………………………………………………………………. 
This research will be coded, and my identity will remain confidential throughout the study. All 
data from physical and supporting examinations and the answers I provide are guaranteed to be 
confidential and will only be used for data processing purposes. I will not receive direct benefits 
from this research, but this research will provide information that can be used as data to present 
scientific evidence that helps clinicians in clinical decision-making regarding the application of 
oral lumbrokinase therapy as part of the causative therapy for BPPV patients, thus it is expected 
to provide valuable information for the advancement of medical science and technology in 
Indonesia, especially in the field related to neuro-oto-ophthalmology. 
My participation in this research will require approximately 30 minutes during my visits to Dr. 
Moewardi Regional General Hospital, Surakarta. 
This participation is voluntary, and I can withdraw as a respondent without any risk if any questions 
cause emotional discomfort or disturbance. 
I have read this consent form and consciously agree to participate in this research. 
Surakarta, ……………………………… 2024 
Respondent,   
 
 
 
 
Witness, 
 
 
………………………………....…   
 
............................................................. 
 
 

REFERENCES 
 
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Jakarta: PT Epidemiologi Indonesia. 
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human utricular otoconia degeneration in vital specimen and implications for benign 
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positional 
vertigo. 
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Arch 
Otorhinolaryngol. 
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3133-8. 
https://doi.org/10.1007/s00405-013-2784-6. 
3. Tang Y, Zhou X, Cao T, Chen E, Li Y, Lei W, Hu Y. 2022. Endoplasmic reticulum stress 
and oxidative stress in inflammatory diseases. DNA Cell Biol. 41(11), 924-34. 
https://doi.org/10.1089/dna.2022.0353. 
4. Güçlütürk MT, Ünal ZN, İsmi O, Çimen MB, Ünal M. 2016. The role of oxidative stress 
and inflammatory mediators in benign paroxysmal positional vertigo. J Int Adv Otol. 12(1), 
101-5. https://doi.org/10.5152/iao.2015.1412. 
5. Andarini M, Murwani CS, Usia T, Setyorini R, Hayati K, Hadiati FT, Sembiring EN. 2020. 
Informatorium Obat Modern Asli Indonesia (OMAI) di Masa Pandemi COVID-19. Badan 
Pengawas Obat dan Makanan, Jakarta. pp. 29-30. 
6. Tjandrawinata RR, Trisina J, Rahayu P, Prasetya LA, Hanafiah A, Rachmawati H. 2014. 
Bioactive protein fraction DLBS1033 containing lumbrokinase isolated from Lumbricus 
rubellus: ex vivo, in vivo, and pharmaceutic studies. Drug Des Devel Ther. 8, 1585-93. 
https://doi.org/10.2147/DDDT.S66007.