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NCT02224456

Efficacy and Safety Study of Tenofovir Disoproxil Fumarate (TDF) in Chinese Chronic Hepatitis B (CHB) Subjects With Advanced Fibrosis & Compensated Cirrhosis

Completed Phase 4 Results posted Last updated 14 February 2022
What this trial tests

Phase 4 trial testing Tenofovir disoproxil fumarate in Hepatitis B, Chronic in 197 participants. Completed in 4 December 2020.

Timeline
25 March 2015
Primary endpoint
4 December 2020
4 December 2020

Quick facts

Lead sponsorGlaxoSmithKline
PhasePhase 4
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment197
Start date25 March 2015
Primary completion4 December 2020
Estimated completion4 December 2020
Sites19 locations across China

Drugs / interventions tested

Conditions studied

Sponsor

GlaxoSmithKline — full company profile →

Who can join

Adults 18 to 60, any sex, with Hepatitis B, Chronic. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Incidence Rate of Newly Diagnosed Hepatocellular Carcinoma (HCC) at Week 240 Primary · Week 240

The newly diagnosed HCC was defined as HCC cases from Week 24 to Week 240 and the participants were required to meet one of the following criteria: without HCC before Week 24; a histological diagnosis of HCC (i.e. by biopsy or at post-mortem); participants with nodules \>2 centimeter (cm), identification of typical HCC characteristics (hyper-vascular in the arterial phase with washout in the portal venous or delayed phases) by 4-phase multi-detector computed tomography (CT) scan or dynamic contrast-enhanced magnetic resonance imaging (MRI); participants with nodules \>1 cm, identification of t

GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg6.045
Percentage of Participants With Disease Progression at Week 240 Primary · Week 240

Disease progression was defined as the first occurrence of any one of the following criteria: 1) an increase in Childs-Pugh score of 2 or more points from Baseline; 2) an increase in Childs-Pugh score of 2 or more points, solely based on laboratory parameters (i.e. bilirubin, prothrombin time and/or albumin) confirmed between two consecutive visits at least one month apart; 3) spontaneous bacterial peritonitis (with proven sepsis); 4) renal insufficiency; 5) bleeding gastric/esophageal varices; 6) hepatocellular carcinoma; 7)liver-related death.

GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg7.2
Number of Participants With Newly Diagnosed Hepatocellular Carcinoma (HCC) at Week 48, Week 96, Week 144 and Week 192 Secondary · Week 48, Week 96, Week 144 and Week 192

The newly diagnosed HCC was defined as HCC cases from Week 24 to Week 240 and the participants were required to meet one of the following criteria: without HCC before Week 24; a histological diagnosis of HCC (i.e. by biopsy or at post-mortem); participants with nodules \>2 centimeter (cm), identification of typical HCC characteristics (hyper-vascular in the arterial phase with washout in the portal venous or delayed phases) by 4-phase multi-detector computed tomography (CT) scan or dynamic contrast-enhanced magnetic resonance imaging (MRI); participants with nodules \>1 cm, identification of t

Week 48
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg0
Week 96
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg0
Week 144
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg4
Week 192
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg9
Percentage of Participants With Newly Diagnosed Hepatocellular Carcinoma (HCC) at Week 48, Week 96, Week 144, Week 192 and Week 240 Secondary · Week 48, Week 96, Week 144, Week 192 and Week 240

The newly diagnosed HCC was defined as HCC cases from Week 24 to Week 240 and the participants were required to meet one of the following criteria: without HCC before Week 24; a histological diagnosis of HCC (i.e. by biopsy or at post-mortem); participants with nodules \>2 centimeter (cm), identification of typical HCC characteristics (hyper-vascular in the arterial phase with washout in the portal venous or delayed phases) by 4-phase multi-detector computed tomography (CT) scan or dynamic contrast-enhanced magnetic resonance imaging (MRI); participants with nodules \>1 cm, identification of t

Week 48
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg0NA – NA
Week 96
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg0NA – NA
Week 144
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg2.10.0 – 4.3
Week 192
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg4.61.4 – 7.8
Week 240
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg5.62.1 – 9.1
Percentage of Participants With Disease Progression at Week 48, Week 96, Week 144, Week 192 and Week 240 Secondary · Week 48, Week 96, Week 144, Week 192 and Week 240

Disease progression was defined as the first occurrence of any one of the following criteria: 1) an increase in Childs-Pugh score of 2 or more points from Baseline; 2) an increase in Childs-Pugh score of 2 or more points, solely based on laboratory parameters (i.e. bilirubin, prothrombin time and/or albumin) confirmed between two consecutive visits at least one month apart; 3) spontaneous bacterial peritonitis (with proven sepsis); 4) renal insufficiency; 5) bleeding gastric/oesophageal varices; 6) hepatocellular carcinoma; 7) liver-related death. The cumulative percentage of participants with

Week 48
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg2.10.0 – 4.3
Week 96
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg2.60.1 – 5.0
Week 144
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg4.11.1 – 7.1
Week 192
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg7.23.3 – 11.1
Week 240
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg7.23.3 – 11.1
Mean Change From Baseline in Liver Stiffness Measure at Week 48, Week 96, Week 144, Week 192 and Week 240 Secondary · Baseline (Day 0), Week 48, Week 96, Week 144, Week 192 and Week 240

Liver stiffness measure was obtained by a non-invasive transient elastography using FibroScan. Baseline is defined as the last assessment (Day 0) before administration of the study drug. Change from Baseline is defined as post-dose visit value minus Baseline value

Week 48, n=182
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-3.3± 4.84
Week 96, n= 176
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-4.7± 5.60
Week 144, n= 175
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-5.1± 5.85
Week 192, n=167
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-5.1± 7.82
Week 240, n= 131
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-6.2± 5.55
Percentage of Participants With Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) <20 International Units Per Milliliter (IU/mL) at Weeks 48, 96, 144, 192 and 240 Secondary · Week 48, Week 96, Week 144, Week 192 and Week 240

Serum samples were collected for the analysis of HBV DNA levels using Roche Cobas Taqman HBV test. Confidence interval was calculated by normal approximation and continuity correction method.

Week 48, n=191
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg81.275.3 – 87.0
Week 96, n=188
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg88.884.1 – 93.6
Week 144, n=185
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg94.190.4 – 97.7
Week 192, n=174
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg97.795.2 – 100.0
Week 240, n=160
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg99.497.8 – 100.0
Change From Baseline in Logarithm to the Base 10 (Log 10) Serum HBV DNA Secondary · Baseline (Day 0) and Week 48, Week 96, Week 144, Week 192 and Week 240

Serum samples were collected for the analysis of HBV DNA levels. Baseline is defined as the last assessment (Day 0) before administration of the study drug. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.

Week 48, n=191
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-4.2± 1.40
Week 96, n=188
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-4.3± 1.44
Week 144, n=185
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-4.3± 1.48
Week 192, n=174
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-4.2± 1.50
Week 240, n=160
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg-4.3± 1.46
Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48, Week 96, Week 144, Week 192 and Week 240 in Participants Who Had Abnormal ALT at Baseline Secondary · Week 48, Week 96, Week 144, Week 192 and Week 240

Blood samples were collected for evaluation of ALT at indicated time points. ALT normalization is defined as ALT outside the normal range at Baseline and within the normal range at Week 48, Week 96, Week 144, Week 192 and Week 240. Normal range of ALT is 7 to 56 International Units per liter. Percentage of participants with ALT normalization at Weeks 48, 96, 144, 192 and 240 in participants who had abnormal ALT at Baseline (Day 0) have been presented. Confidence interval was calculated using normal approximation and continuity correction method.

Week 48, n=97
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg63.953.8 – 74.0
Week 96, n= 97
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg66.056.0 – 75.9
Week 144, n=96
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg70.861.2 – 80.4
Week 192, n=93
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg82.874.6 – 91.0
Week 240, n=87
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg82.874.2 – 91.3
Percentage of Hepatitis B e Antigen (HBeAg) Positive Participants Achieving HBeAg Loss, HBeAg Seroconversion at Week 48, Week 96, Week 144, Week 192 and Week 240. Secondary · Week 48, Week 96, Week 144, Week 192 and Week 240

Serological response was assessed at Week 48, Week 96, Week 144, Week 192 and Week 240 in participants with Positive HBeAg at Baseline (Day 0). It was presented as HBeAg Loss and HBeAg Seroconversion. HBeAg Loss was defined as HBeAg changed to be negative. HBeAg seroconversion was defined as HBeAg changed to negative and HBeAb was positive. Confidence interval was calculated using normal approximation and continuity correction method.

Week 48, HBeAg Loss, n=94
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg18.19.8 – 26.4
Week 48, HBeAg Seroconversion, n=94
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg9.63.1 – 16.1
Week 96, HBeAg , n=94
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg33.022.9 – 43.0
Week 96, HBeAg Seroconversion, n=94
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg14.97.2 – 22.6
Week 144, HBeAg Loss, n=90
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg35.624.5 – 45.1
Week 144, HBeAg Seroconversion, n=90
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg14.46.5 – 21.8
Week 192, HBeAg Loss, n=90
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg47.836.4 – 58.1
Week 192, HBeAg Seroconversion, n=90
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg16.78.3 – 24.7
Percentage of HBeAg Negative Participants Achieving HBsAg Loss and HBsAg Seroconversion at Week 48, Week 96, Week 144, Week 192 and Week 240 Secondary · Week 48, Week 96, Week 144, Week 192 and Week 240

Serological response was assessed at Week 48, Week 96, Week 144, Week 192 and Week 240 in participants with negative HBeAg at Baseline (Day 0). HBsAg Loss was defined as HBsAg changed to be negative. HBsAg seroconversion was defined as HBsAg changed to negative and HBsAb was positive.

Week 48, HBsAg Loss, n=97
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg1.00.0 – 3.6
Week 48, HBsAg Seroconversion, n=97
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg1.00.0 – 3.6
Week 96, HBsAg , n=93
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg00.0 – 0.5
Week 96, HBsAg Seroconversion, n=93
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg00.0 – 0.5
Week 144, HBsAg Loss, n=93
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg3.20.0 – 7.4
Week 144, HBsAg Seroconversion, n=93
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg00.0 – 0.5
Week 192, HBsAg Loss, n=89
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg4.50.0 – 9.4
Week 192, HBsAg Seroconversion, n=89
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg2.20.0 – 5.9
Percentage of Participants Who Experienced Viral Breakthrough Secondary · Week 48, Week 96, Week 144, Week 192 and Week 240

Viral breakthrough was defined as \>=1 log10 increase in HBV DNA from nadir determined by two sequential HBV DNA measurements. Percentage of Participants who experienced viral breakthrough at Week 48, Week 96, Week 144, Week 192 and Week 240 is presented.

Week 48, n=195
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg0NA – NA
Week 96, n=195
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg0NA – NA
Week 144, n=185
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg0.50.0 – 1.9
Week 192, n=180
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg1.10.0 – 2.9
Week 240, n=161
GroupValue95% CI
Tenofovir Disoproxil Fumarate 300 mg0.60.0 – 2.1

Adverse events — posted to ClinicalTrials.gov

Time frame: All cause mortality, non-serious TEAEs and serious TEAEs were collected up to 240 weeks from the start of the treatment.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Tenofovir Disoproxil Fumarate 300 mg
Serious: 34/195 (17%)
Deaths: 2/195

Serious adverse events (29 terms)

ReactionSystemTenofovir Disoproxil Fumar…
Hepatocellular carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
CholelithiasisHepatobiliary disorders
Malignant melanomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian germ cell teratomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Foot fractureInjury, poisoning and procedural complications
Lower limb fractureInjury, poisoning and procedural complications
Post procedural bile leakInjury, poisoning and procedural complications
Radius fractureInjury, poisoning and procedural complications
Spinal compression fractureInjury, poisoning and procedural complications
Tibia fractureInjury, poisoning and procedural complications
Bile duct stoneHepatobiliary disorders
CholecystitisHepatobiliary disorders
Cholecystitis acuteHepatobiliary disorders
Hepatic cirrhosisHepatobiliary disorders
PneumoniaInfections and infestations
Upper respiratory tract infectionInfections and infestations
Rheumatic feverMusculoskeletal and connective tissue disorders
Synovial cystMusculoskeletal and connective tissue disorders
Nasal polypsRespiratory, thoracic and mediastinal disorders
Nasal septum deviationRespiratory, thoracic and mediastinal disorders
Rhinitis hypertrophicRespiratory, thoracic and mediastinal disorders
UrticariaSkin and subcutaneous tissue disorders
Vertigo positionalEar and labyrinth disorders
Uterine adhesionsReproductive system and breast disorders
UreterolithiasisRenal and urinary disorders
Other adverse events (133 terms — click to expand)

ReactionSystemTenofovir Disoproxil Fumar…
Upper respiratory tract infectionInfections and infestations
HypophosphataemiaMetabolism and nutrition disorders
Urinary tract infectionInfections and infestations
Blood creatine phosphokinase increasedInvestigations
AnaemiaBlood and lymphatic system disorders
HypocalcaemiaMetabolism and nutrition disorders
AscitesGastrointestinal disorders
ToothacheGastrointestinal disorders
CholelithiasisHepatobiliary disorders
HypertensionVascular disorders
DiarrhoeaGastrointestinal disorders
Protein urine presentInvestigations
Back painMusculoskeletal and connective tissue disorders
NasopharyngitisInfections and infestations
Abdominal painGastrointestinal disorders
Abdominal pain upperGastrointestinal disorders
Blood phosphorus decreasedInvestigations
Alpha 1 foetoprotein increasedInvestigations
NephrolithiasisRenal and urinary disorders
Renal impairmentRenal and urinary disorders
Rhinitis allergicRespiratory, thoracic and mediastinal disorders
RashSkin and subcutaneous tissue disorders
Transaminases increasedInvestigations
HypokalaemiaMetabolism and nutrition disorders
PharyngitisInfections and infestations
PneumoniaInfections and infestations
Pulmonary tuberculosisInfections and infestations
GastritisGastrointestinal disorders
DyspepsiaGastrointestinal disorders
Epigastric discomfortGastrointestinal disorders
Abdominal distensionGastrointestinal disorders
Gastric ulcerGastrointestinal disorders
FlatulenceGastrointestinal disorders
Chronic gastritisGastrointestinal disorders
NauseaGastrointestinal disorders
Blood urine presentInvestigations
Weight decreasedInvestigations
Blood uric acid increasedInvestigations
HyperglycaemiaMetabolism and nutrition disorders
Iron deficiency anaemiaBlood and lymphatic system disorders

Most-reported serious reactions: Hepatocellular carcinoma, Cholelithiasis, Malignant melanoma, Ovarian germ cell teratoma, Foot fracture, Lower limb fracture, Post procedural bile leak, Radius fracture.

Data from ClinicalTrials.gov NCT02224456 adverse events section.

Sponsor's own description

Chronic Hepatitis B infection (CHB) is known as the most frequently identified cause of liver disease that predisposes patients to the development of hepatocellular carcinoma (HCC). Active hepatitis B virus (HBV) replication is the key driver of liver injury and disease progression. Majority of Chinese patients are infected with genotype B and C HBV, which is different from Caucasian counterparts. This prospective multi-center cohort open-label study is designed to investigate the long-term effect of TDF on prevention of HCC and disease progression as well as to evaluate the efficacy and safety of long-term TDF in Chinese CHB subjects with advanced liver diseases. The study will enrol 240 subjects.

Publications & conference data

4 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine.
    Fujiwara N, Friedman SL, Goossens N, Hoshida Y. · · 2018 · cited 519× · PMID 28989095 · DOI 10.1016/j.jhep.2017.09.016
  2. Generic chemoprevention of hepatocellular carcinoma.
    Athuluri-Divakar SK, Hoshida Y. · · 2019 · cited 18× · PMID 30221358 · DOI 10.1111/nyas.13971
  3. Spontaneous bacteremia and spontaneous bacterial peritonitis share similar prognosis in patients with cirrhosis: a cohort study.
    Marciano S, Dirchwolf M, Bermudez CS, Sobenko N, et al · · 2018 · cited 15× · PMID 29224053 · DOI 10.1007/s12072-017-9837-7
  4. Tenofovir disoproxil fumarate therapy in patients with chronic hepatitis B and advanced fibrosis or compensated cirrhosis.
    Rao H, Shang J, Xie Q, Lian J, et al · · 2022 · cited 1× · PMID 40636795 · DOI 10.1016/j.iliver.2022.08.006

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