Randomized Trial of Tenofovir Disoproxil Fumerate Dose Adjustment VS. Switching to Tenofovir Alafenamide in Tenofovir Disoproxil Fumarate-experienced Chronic Hepatitis B Patients With Renal Impairment
Phase: PHASE4
Conditions: Renal Insufficiency, Tenofovir
Sponsor: Mahidol University

 
 
 
 
 
 
 
Randomized trial of  
tenofovir disoproxil fumerate dose adjustment VS. switching to tenofovir alafenamide  
in tenofovir disoproxil fumarate-experienced chronic hepatitis B patients with renal impairment 
 
 
 
SIRB Protocol No. : 657/2562(EC3) 
COA no. : SI 798/2019 
Document date : 25 Nov 2019 
 
 
 
 

Study protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Volunteers that meet the screening criteria will receive a research explanation. If they be willing to 
participate in this study, enrollment is performed 
N = 80 
Block of 4 randomization 
TDF dose adjustment (N=40) 
TAF 25 mg/day (N=40) 
- Demographic data such as age, sex, weight, height, body mass index, blood pressure, medical conditions, 
organ transplantation, kidney replacement therapy 
- Collect information about the use of various drugs such as personal medicine, NSAIDs 
- Draw blood 20 ml for laboratory examination including complete blood count (CBC), liver function test, 
creatinine, blood urea nitrogen, electrolyte, serum calcium, serum phosphate, Uric acid,  
- Urine collection including urinalysis, urine protein creatinine ratio, urine ß2-microglobulin, urine 
phosphate and urine NGAL 
- Follow-up at least every 12 weeks (+/- 7 days) until 
week 48.  
- Symptom monitoring, physical examination, drug 
adherence, body mass index, blood pressure  
- sent laboratory examination shown in the attached table 
At 48 wk ; Analyzed for primary and secondary outcome 

 
Week 0 
Week 12 
Week 24 
Week 36 
Week 48 
History taking and physical 
examination 
X 
X 
X 
X 
X 
CBC 
X 
 
 
 
X 
Creatinine, BUN, Uric acid, 
Calcium, Phosphate, 
Electrolyte 
X 
X 
X 
X 
X 
AST/ALT 
X 
X 
X 
X 
X 
HBV DNA viral load 
 
 
X 
 
X 
urinalysis, urine protein 
creatinine ratio, urine 
phosphate 
X 
X 
X 
X 
X 
urine ß2-microglobulin 
X 
X 
X 
 
X 
urine NGAL 
X 
X 
 
 
 
ultrasonography of upper 
abdomen 
 
 
X 
 
X 
 
- Some blood tests may be stored before -20 ° C for later tests. 
- Some urine tests may be stored before -30 ° C for later tests. 
 
Monitoring and follw-up guidelines in the event that patients receiving TDF dose adjustment or 
change to TAF and the kidney function deterioration. 
- If the GFR from 40 ml/min or more: Make appointment for examination every 12 weeks 
- If the GFR is less than 40 ml/min: Make appointment every month 

- If the GFR is less than 30 ml/min: Change to Entecavir (1mg) 1 * 1 po pc 
 
If patient will have to check up earlier than 12 weeks, there will be a travel cost of 300 baht per time. 
However, if the patient comes to the same appointment every 12 weeks, there will be no travel cost. 
 
Inclusion criteria 
1. Age between 18 - 75 years old  
2. Chronic hepatitis B virus infection 
3. Reduced renal function and need to adjust the dose of TDF 
4. Have an eGFR of > 15 ml / min.  
5. HBV DNA viral load levels < 10 U/mL in the last 3 months before participating in the project  
6. No HCC by ultrasonography of the upper abdomen or CT 3-phase of liver or MRI liver in the 3 months 
before participating in the project. 
Exclusion criteria 
1. HIV infection or hepatitis C or hepatitis D co-infection 
2. Decompensated cirrhosis, including variceal bleeding, ascites, hepatic encephalopathy 
3. Active hepatocellular carcinoma or during the 3 years after treatment 
4. Solid organ transplantation or Bone marrow transplantation 
5. Chronic kidney disease caused by glomerulonephritis, tubulo-interstitial nephritis), Obstructive 
uropathy or autosomal dominant polycystic kidney, and Kidney disease from other causes 
6. Diabetes with HbA1c> 8 or uncontrollable hypertension 
7. Active malignancy of cancer in other organs in the last 3 years 
8. History of receiving non-steroidal anti-inflammatory drugs (NSAIDs) or other nephrotoxic drugs within 
the past 1 month (except tenofovir) 

(For patients receiving NSAIDS after participating in this study, patients were advised to stop taking 
NSAIDs but not exclude from the study) 
9. Receive immunosuppressive drug  
10. Pregnancy 
 
Withdrawal or termination criteria 
1. GFR reduction was less than 15 ml / min 
2. Receive renal replacement therapy 
3. Receive a liver or kidney organ transplant. 
4. Request to withdraw from their participation in the study. 
5. Develop HCC. 
 
Sample size calculation 
 
From a literature review, It was found that the average value of the eGFR level of the TDF 
group was -5.34 ± 7.69 (n = 45) (95% CI: -7.65 - -3.02) and the mean value of the eGFR in TAF group 
was +2.89. ± 4.26 (n = 36) (95% CI: 1.45 - 4.33) But from the Siriraj hospital observations during 2018, 
the mean The eGFR change value level is +5.92 after TDF dose adjustment. Therefore, from the above 
data, when determining the significance level = 0.05 (type I error = 5%, 2-sided) and power of the test = 
80% (type II error = 20%), 33 samples would be needed in each group 
 


2
2
1
2
2
2
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(
)
(






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Z
Z
n
 
เมื่อ 

n  samples would be needed in each group 
 

 type I error = 0.05
)
96
.1
(
2
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
Z
 


 type II error = 0.20 
)
84
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Z
 
 
 
= standard deviation 
 
2
1


=  The difference of mean values between groups 
 
 
 

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2
2
2
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89
.2
92
.5
(
)
26
.4
(
84
.0
96
.1
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
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n
 =  33  
 
From the calculations, it was found that at least 33 samples were used per group. After add 
dropout rate 15%, So 40 samples are to be used per group, a total of 80 people in this study.  
Statistical analysis 
 
8.8.1 Descriptive statistics 
 
Demographic data such as qualitative variables such as gender, presented in frequency and 
percentage.  
 
The quantitative variables, such as age, that are continuous data, presented with the mean and 
standard deviation (SD) if the data has a normal distribution. However, if the data doesn't have a normal 
distribution, presented with the median and minimum-maximum values. 
 
8.8.2 Inferential statistics 
 
- Comparison of changes in eGFR, serum phosphate, urine protein creatinine ratio, urine 
phosphate, urine ß2-microglobulin, AST, ALT, HBV DNA between the treatment with TAF and adjusted 
dose TDF for 48 weeks by using the Repeated measures ANOVA or Friedman's test. 
 
- Comparison of the change in urine NGAL between the treatment with TAF and adjusted dose 
TDF for 48 weeks by using Independent T test or Mann whitney test 
 
 
Data recording and analysis using SPSS programme