Vitamin D Supplementation Effect In Children With Pulmonary Tuberculosis Treatment: Randomized Double Blind Controlled Trial
Phase: NA
Conditions: Tuberculosis, Pulmonary
Sponsor: Universitas Padjadjaran

Research Title: Vitamin D Supplementation Effect In Children With Pulmonary Tuberculosis Treatment: 
Randomized Double Blind Controlled Trial 
 
Principal Investigator: dr. Lianda Tamara, Sp.A 
Expertise: Pediatrics 
Position: Doctoral Student 
E-mail: tamaralianda@gmail.com 
Institution: Program Pascasarjana Program Studi Doktor Fakultas Kedokteran Universitas Padjadjaran 
Institution e-mail: humas.fk@unpad.ac.id 
Sponsor: Individual (Principal Investigator) 
 
Clinical Monitor: Dr. dr. Fushen, M.H., M.M., FISQua 
 
Investigator teams: 
Prof. Dr. Dida A.Gurnida, dr., Sp.A(K), M.Kes 
Prof.Dr.Cissy B.Kartasamita, dr., Sp.A(K), M.Sc Ph.D 
Dr.Anggraini Alam, dr., Sp.A(K) 
 
Disclaimers: The investigators have no potential conflict of interest 
 
Source(s) of support/funding: No funding or other financial support was received. 
 
Disclosure of relationships and activities: none declared 
 
Ethical issues: The contributing investigators have no potential ethical issues. 
 
Document Last Update Date: 1 June 2021 
 
 
 

Summary of Clinical Trial Protocol 
 
Study Description: 
This randomized, double-blind control trial with a cohort design was conducted in Bethesda Hospital West 
Borneo from December 2020 - May 2021. The inclusion criteria were children between 6 to 18 years old, 
newly diagnosed with pulmonary tuberculosis with vitamin D insufficiency. Diagnosis of the tuberculosis 
case was based on The Indonesian Pediatric Tuberculosis Scoring System. It consists of history taking and 
laboratory findings that support tuberculosis common symptoms such as household contact, prolonged 
fever more than two weeks, non-remitting cough more than three weeks, and decrease body weight, and 
lymph node enlargement; laboratory findings include Tuberculin Skin Test (TST) and chest X-ray (CXR). 
Scoring ranges from 0 to 3 for each variable with a total score of more than six is considered as tuberculosis 
diagnosis. Patients also collect the sputum for gram staining and Xpert MTB/RIF examination. The isolation 
of Mycobacterium tuberculosis was not done in this study because of limited resources. 
 
Subject selection was determined based on consecutive sampling, namely the order of patients who came 
to the clinic until the minimum sample size (84 subjects) met the inclusion criteria. The exclusion criteria 
are children with a history of liver or kidney abnormalities, immunocompromised, and already received 
vitamin D supplementation. After obtaining written consent, all subjects had their blood specimens drawn 
3cc from the brachial vein to measure alanine transaminase (ALT), alkaline phosphatase (ALP), serum 
active 25-hydroxyvitamin D using the ELISA method. Vitamin D is categorized as deficiency if serum 25-
hydroxyvitamin D is below 20ng/mL, insufficiency between 20─30ng/mL, and normal levels above 
30ng/mL. In this study, the 95% confidence level (Zα = 1.65 one-sided test) and 80% power test (Zß = 0.84) 
were selected. The calculation of the sample size above obtained n = 35 people for each group. The total 
study subjects were added by 20% of the minimum number of samples to compensate for loss-to-follow-
up, so the total sample was 84, consisting of 42 patients in the intervention group and 42 patients in the 
placebo group. 
 
For each subject, the following data were entered into the study database demographic data ( name, age, 
sex), signs and symptoms (fever, cough), Tuberculin Skin Test (TST), Chest X-Ray, and also GeneXpert for 
Mycobacterium tuberculosis from gastric lavage or sputum induction, liver function test and 25-
hydroxyvitamin D level. All results were recorded in a study database following international standards to 
protect the privacy and personal information. 
 
Subjects were randomly assigned to receive either a 1000IU vitamin D supplement dose or a placebo with 
an allocation ratio of one to one. Before starting recruitment, the project manager prepared 84 packs of 
study preparation - 42 packs of the active study drug and 42 packs of a placebo, then generated a 
randomization sequence using a computer program assigning the terms active or placebo to numbers 1 
to 84. The packs were then assigned a randomized number according to this computer-generated 
randomization sequence. 
 
At recruitment, study staff enrolled patients consecutively according to the order of arrival of patients 
from number 1 to 84. Study staff who assigned patients to active drugs or placebo did not know the 
following assignment in the sequence because they did not have access to the study code. Treatment 
allocations were hidden from patients and research staff. Those who analyzed the data were not covered 
for group assignments. Monitoring of subjects medication adherence and daily symptoms conducted by 
using a checklist table filled out by the patient's parents and confirmed check by the researcher during 
the patient follow-up schedule to the clinic. 
 

All subjects received antimicrobial treatment for tuberculosis drugs in the form of a fixed-dose 
combination. Patients were reviewed on 14, 28, 42, and 56 days after starting antimicrobial treatment; 
body weight and height were measured at each time point. After the intensive phase of antimicrobial 
treatment, patients were monitored monthly. A repeated vitamin D level by ELISA and liver function test 
were done six months after starting the antimicrobial treatment. 
 
Clinical Trial Process 
a) Administration of intervention (dose regimen, invasive and non-invasive measures, comparison drugs, 
placebo): Pediatric patients diagnosed with TB and vitamin D insufficiency will be given vitamin D 
supplementation of 1000IU/day for six months. Giving a placebo in the control group will get one dose 
of placebo/day for six months. Vitamin D and placebo preparations are prepared in the same colored 
bottles containing vitamin D or a placebo. 
 
b) Determination of outcome indicators: 
After six months of treatment, the patient will have his vitamin D level checked. 
 
c) Interim analysis plan: sputum examination is performed every two weeks during the intensive phase 
of antituberculosis treatment. 
 
d) Clinical trial termination procedure: 
Parents of patients who refuse to be included in this study can stop the administration of vitamin D 
supplementation by reporting to the doctor in charge of the service during control at the pediatric 
outpatient clinic at Bethesda Hospital, West Kalimantan. Patients who do not complete treatment for six 
months (including unexpected events) will be discontinued from participating in the study and explained 
to parents that TB treatment is continued but not included in the study, and the test drug package will 
not be continued. 
 
e) Estimated research time required for one subject per one course of action: 5 minutes per action of 
blood and phlegm examination. 
 
f) Ethical issues (state your opinion on ethical issues in research that may be encountered): 
• Respect for someone (respect for human dignity): 
Researchers provide information to parents of research to be carried out, including procedures, 
benefits, risks, volunteering, and data confidentiality. Information is provided so that the subject's 
parents can determine whether their child can participate in the study or not. Parents are free to make 
their own decisions. Subjects' parents who voluntarily participated in this study were then asked to 
express written consent by signing informed consent. 
 
• Beneficence (beneficial) non-maleficence (not harmful): 
There is no physical risk to the child who is the subject of the study, but it can cause it to occur. The 
benefits of this research are not felt directly by the child/parent. However, the willingness to be a 
subject will be significant to obtain information on routine vitamin D levels in children with tuberculosis. 
It can be used as input and the essential information to provide vitamin D supplementation in children 
with tuberculosis. Suppose the examination results reveal a vitamin D deficiency. In that case, the child 
will receive vitamin D supplementation at no charge to the parents. 
 
 
 

• Justice (fairness): 
All subjects are treated equally in the study and are given the same opportunity to be included, which is 
carried out in a fair and balanced manner. 
 
Adverse Event (AE) reporting plan 
a. Recording (Things to be reported): symptoms of side effects of antituberculosis treatment such as 
jaundice, nausea, and vomiting. 
b. Analysis and procedure of action: the patient will be examined for liver function. If the liver function 
increases, antituberculosis drugs will be discontinued. 
c. Emergency rescue system: patients who feel there are complaints of nausea, vomiting, and jaundice 
will go to the Children's Clinic, Bethesda Hospital, West Kalimantan. 
d. Discontinuation of subjects in the study due to adverse events: the administration of antituberculosis 
drugs will be discontinued, and patients will not be included in the study. 
 
 

INFORMATION (Translated from Bahasa Indonesia) 
 
VITAMIN D SUPPLEMENTATION EFFECT IN CHILDREN WITH PULMONARY TUBERCULOSIS TREATMENT: 
RANDOMIZED DOUBLE BLIND CONTROLLED TRIAL 
 
I am a pediatrician from Bethesda Hospital, West Kalimantan, who is conducting a study to assess the 
administration of vitamin D3 supplementation in pediatric tuberculosis patients; I invite you to participate 
in this study, your participation in this study is voluntary, so you can decide to participate or vice versa. 
 
Research purposes: 
Vitamin D is a vital substance needed by a child's body. Vitamin D deficiency in your child can lead to 
impaired optimal growth and development. This study aims to assess the administration of vitamin D3 
supplementation in pediatric TB patients receiving TB treatment. 
Why Subject was selected: 
Your child was selected to be included in this study because your child is a tuberculosis patient and is 
receiving treatment at the Children's Polyclinic, Bethesda Hospital, West Borneo. 
 
Procedures/Procedures: 
Suppose you agree that your child is included in this study. In that case, your child will have 2 mL of blood 
taken at the Bethesda Hospital West Kalimantan laboratory to check vitamin D levels. If the vitamin D 
level is between 21-29 ng/mL, it will be included in the study. Your child will receive medicine in the form 
of vitamin D or sugar-coated drugs according to the serial number listed. Vitamin D drug in the form of 
syrup, taken in the morning as much as 2.5 mL once a day. Sputum collection was carried out every two 
weeks for the first two months of treatment. After your child has undergone six months of tuberculosis 
treatment, a re-examination of the vitamin D level will be evaluated by taking 2 mL of blood. 
 
Risks and inconveniences: 
The risk in this study was only found when your child was taken for blood, namely pain at the blood 
collection location. Other risks associated with this study were not found in the literature. 
 
Benefits (direct to the subject and general): 
The benefit of this research for your child is to determine the level of vitamin D in your child and get 
vitamin D supplementation. Giving vitamin D supplementation for six months does not have any side 
effects for your child. Suppose your child's vitamin D level is still low after six months of treatment. In that 
case, vitamin D supplementation will be given until the vitamin D level is >30 ng/mL. 
 
Data confidentiality: 
As long as your child participates in this research, any information and data will be treated confidentially. 
It is not possible for others to know. 
 
Estimated number of subjects to be included: 
The number of children who will be included in this study is 84 children. 
 
Volunteering: 
Your child's participation in this research is voluntary with responsibility until the completion of this 
research. 
 
 

Subject Participation Period: 
Your child's participation in this study is for six months. 
 
Subjects may be excluded/resigned from the study: 
You are free to refuse to participate in this research. If you have decided to include your child, you can 
also resign without causing a change in the quality of doctor's services if you are sick. However, suppose 
your child does not follow and fulfill the procedures given by the researcher. In that case, your baby's 
participation in this study will end. 
 
Possible financing from health insurance companies or researchers: 
The researcher will bear all costs of this research. 
 
Incentives and compensation: 
For your child's participation in this study, incentives will be given in the form of souvenirs as a token of 
gratitude, and no compensation in any form will be given. 
 
Question: 
If there are any questions related to this research to dr. Lianda Tamara, Sp.A at Bethesda Hospital, West 
Borneo, Mobile Phone. 081223811821 
 
 

 
Informed Consent for Parents/Guardian 
 
INFORMED CONSENT 
TO PARTICIPATE IN RESEARCH 
WITH CHILD SUBJECT  
(Translated from Bahasa Indonesia) 
 
I have read or obtained an explanation, am fully aware, understand, and understand the objectives, 
benefits, and risks that may arise in the research, and have been given the opportunity to ask questions 
and have been answered satisfactorily, and may withdraw my child/sister at any time. from their 
participation, then I agree/disagree*) participate in this research, entitled:  
 
“Vitamin D Supplementation Effect In Children With Pulmonary Tuberculosis Treatment: 
Randomized Double Blind Controlled Trial”  
 
I voluntarily choose my child/sister to participate in this research without any pressure/coercion from 
anyone. I will be given a copy of the explanation sheet and consent form that I have signed for my file. 
I agree: 
Yes/No*) 
 
 
Date:  
 
Signature or Fingerprints 
Child name: 
Age: 
Address: 
 
 
Parents/Guardian name: 
 
 
 
Principal Investigator: 
  
 
 
Witnesses name: 
 
 
 
 
*) select the appropriate 
 
 
 
 
 
 
 
 
 

 
 
Informed Consent for Child 
12> – < 18 years old 
 
APPROVAL AFTER EXPLANATION (PSP) 
TO PARTICIPATE IN RESEARCH 
WITH CHILD SUBJECT  
 (ASSENT) 
(Translated from Bahasa Indonesia) 
 
I have read or obtained an explanation, am fully aware, understand, and understand the objectives, 
benefits and risks that may arise in the research, and have been given the opportunity to ask questions 
and have been answered satisfactorily, and may at any time withdraw from my participation. I 
agree/disagree*) participate in this research, entitled:  
 
“Vitamin D Supplementation Effect In Children With Pulmonary Tuberculosis Treatment: 
Randomized Double Blind Controlled Trial”  
 
I voluntarily choose to participate in this research without any pressure/coercion from anyone. I will be 
given a copy of the explanation sheet and consent form that I have signed for my file. 
I agree: 
Yes No*) 
 
 
Date:  
 
Signature or Fingerprints 
Child name: 
Age: 
Address: 
 
 
Parents/Guardian name: 
 
 
 
Principal Investigator: 
  
 
 
Witnesses name: 
 
 
 
 
*) select the appropriate