Clinical Trial Results:
A Study of the Safety and Efficacy of Entecavir plus Tenofovir in Adults with Chronic Hepatitis B Virus Infection with Previous Nucleoside/Nucleotide Treatment Failure
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Summary
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EudraCT number |
2009-015705-40 |
Trial protocol |
NL IT DE FR |
Global end of trial date |
18 Feb 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Apr 2016
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First version publication date |
01 Apr 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AI463-203
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01063036 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bristol-Myers Squibb
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Sponsor organisation address |
Bristol-Myers Squibb International Corporation, Chaussée de la Hulpe 185, Brussels, Belgium, 1170
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Public contact |
Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
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Scientific contact |
Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Feb 2014
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Feb 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of the study was to describe the efficacy of the combination therapy of Entecavir plus Tenofovir Disoproxil Fumarate at 48 weeks of treatment, in control of viral load Hepatitis B Virus (HBV) DNA <50 IU/mL in chronic HBV infected subjects who have failed previous treatment.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 May 2010
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
6 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 9
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Country: Number of subjects enrolled |
Poland: 43
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Country: Number of subjects enrolled |
Romania: 30
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Country: Number of subjects enrolled |
France: 16
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Country: Number of subjects enrolled |
Germany: 43
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Country: Number of subjects enrolled |
Italy: 3
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Worldwide total number of subjects |
144
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EEA total number of subjects |
144
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
129
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From 65 to 84 years |
15
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85 years and over |
0
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Recruitment
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Recruitment details |
Study initiated 17 May 2010; Week 48 Primary Endpoint 27 November 2012; Week 96 Study Completed 18 February 2014. Subjects with chronic Hepatitis B with surface antigen who have been currently treated and experienced treatment failure were enrolled. | ||||||||||||||||||
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Pre-assignment
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Screening details |
144 enrolled; 92 treated. Reasons for 52 never treated: physical/laboratory test findings 30; not in target population 21; no signed consent 7; medical history/concurrent disease 2; other exclusion criteria 1; unknown 3. | ||||||||||||||||||
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Period 1
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Period 1 title |
Subjects Treated With Study Drug
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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Entecavir + Tenofovir | ||||||||||||||||||
Arm description |
Entecavir: Tablets, Oral, 1 mg, once daily, 96 weeks. Tenofovir disoproxil fumarate: Tablets, Oral, 300 mg, once daily, 96 weeks. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Entecavir
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Investigational medicinal product code |
BMS-200475
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Other name |
Baraclude®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Entecavir: Tablets, Oral, 1 mg, once daily, 96 weeks.
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Investigational medicinal product name |
Tenofovir
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Investigational medicinal product code |
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Other name |
Viread®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tenofovir disoproxil fumarate: Tablets, Oral, 300 mg, once daily, 96 weeks.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Out of the 144 enrolled, only 92 subjects were treated. Reasons for 52 never treated: physical/laboratory test findings 30; not in target population 21; no signed consent 7; medical history/concurrent disease 2; other exclusion criteria 1; unknown 3. Few subjects had more than one reason for not being treated. |
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Period 2
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Period 2 title |
Post Dosing Follow-up Through 24 Weeks
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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Entecavir + Tenofovir | ||||||||||||||||||
Arm description |
Entecavir: Tablets, Oral, 1 mg, once daily, 96 weeks. Tenofovir disoproxil fumarate: Tablets, Oral, 300 mg, once daily, 96 weeks. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Entecavir
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Investigational medicinal product code |
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Other name |
Baraclude®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Entecavir: Tablets, Oral, 1 mg, once daily, 96 weeks.
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Investigational medicinal product name |
Tenofovir
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tenofovir disoproxil fumarate: Tablets, Oral, 300 mg, once daily, 96 weeks.
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| Notes [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Of the 86 subjects who completed treatment, 3 subjects were lost to follow-up, but 2 subjects who did not complete treatment went into the post-dosing phase, bringing the total entering follow-up to 85 subjects. |
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Baseline characteristics reporting groups
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Reporting group title |
Entecavir + Tenofovir
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Reporting group description |
Entecavir: Tablets, Oral, 1 mg, once daily, 96 weeks. Tenofovir disoproxil fumarate: Tablets, Oral, 300 mg, once daily, 96 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Entecavir + Tenofovir
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Reporting group description |
Entecavir: Tablets, Oral, 1 mg, once daily, 96 weeks. Tenofovir disoproxil fumarate: Tablets, Oral, 300 mg, once daily, 96 weeks. | ||
Reporting group title |
Entecavir + Tenofovir
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Reporting group description |
Entecavir: Tablets, Oral, 1 mg, once daily, 96 weeks. Tenofovir disoproxil fumarate: Tablets, Oral, 300 mg, once daily, 96 weeks. | ||
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End point title |
Percentage of Subjects With a Virologic Response at Week 48 - Treated Population [1] | ||||||||
End point description |
Virologic response was defined as Hepatitis B virus (HBV) DNA <50 IU/mL; approximately 300 copies/mL. Percentage was calculated using non-completer=failure, defined as the number of subjects with virologic response at Week 48 divided by the number of treated subjects. An exact binomial 95% confidence interval was constructed. HBV DNA by polymerase chain reaction was measured in using the Roche COBAS(REGISTERED) TaqMan - High Pure System assay in IU/mL, with the limit of quantification=29 IU/mL and lower limit of detection=6 IU/mL. All treated subjects were analyzed.
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End point type |
Primary
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End point timeframe |
Week 48
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single-arm estimation study in which the primary end point is assessed with proportions. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With a Virologic Response at Week 24 and at Week 96 - Treated Population | ||||||||||||
End point description |
Virologic response was defined as Hepatitis B virus (HBV) DNA <50 IU/mL; approximately 300 copies/mL. Percentage was calculated using non-completer=failure, defined as the number of subjects with virologic response at Week 24, Week 96 divided by the number of treated subjects. An exact binomial 95% confidence interval was constructed. HBV DNA by polymerase chain reaction was measured using the Roche COBAS(REGISTERED) TaqMan - High Pure System assay in IU/mL, with the limit of quantification=29 IU/mL and lower limit of detection=6 IU/mL. All treated subjects were analyzed.
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End point type |
Secondary
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End point timeframe |
Week 24, Week 96
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Mean log10 Hepatitis B Virus DNA at Weeks 12, 24, 48, and 96 - Treated Evaluable Population | ||||||||||||||||
End point description |
Hepatitis B Virus (HBV) DNA by polymerase chain reaction was measured in IU/mL using the Roche COBAS(REGISTERED) TaqMan - High Pure System assay, with the limit of quantification (LOQ)=29 IU/mL and lower limit of detection=6 IU/mL. HBV DNA measurements were transformed by log10, using log10(LOQ-1) for values below LOQ. Baseline was last measurement before or on Day 1 of study drug. All treated subjects with results at both baseline and on-treatment were analyzed. n=number of treated subjects with results at baseline and Week 12, Week 24, Week 48 and Week 96.
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End point type |
Secondary
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End point timeframe |
Baseline to Weeks 12, 24, 48, 96
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage of Subjects With Hepatitis B Virus DNA Less Than the Lower Limit of Detection (LLD) at Weeks 24, 48, and 96 - Treated Population | ||||||||||||||
End point description |
HBV DNA <LLD (6 IU/mL) was defined/measured by the COBAS (REGISTERED) TaqMan High Pure System assay at Weeks 24, 48, and 96. Percentage was calculated using non-completer=failure, defined as number of subjects with HBV DNA <LLD at Weeks 24, 48, 96 divided by the number of treated subjects. An exact binomial 95% confidence interval was constructed. All treated subjects were analyzed.
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End point type |
Secondary
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End point timeframe |
Weeks 24, 48, 96
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Subjects With Hepatitis B e Antigen (HBeAg) Loss at Weeks 24, 48, and 96 - Treated Population Who Were HBeAg Positive at Baseline | ||||||||||||||
End point description |
Loss of HBeAg was defined as being HBeAg-negative at Weeks 24, 48, and 96 in those subjects who had been HBeAg-positive at baseline. Method used for HBeAg was DiaSorin - Anti HBe enzyme immunoassay kit – procedure for qualitative determination of antibodies to HBeAg in human serum or plasma samples. Percentage was calculated using non-completer=failure, defined as number of subjects with HBeAg loss at Weeks 24 and 48 divided by the number of treated subjects who were HBeAg-positive at baseline. An exact binomial 95% confidence interval was constructed. Baseline was the last measurement before or on Day 1 of study drug. All treated subjects who were HBeAg-positive at baseline were analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline to Weeks 24, 48, and 96
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Subjects With Hepatitis B e (HBe) Seroconversion at Weeks 24, 48, and 96 - Treated Population Who Were Hepatitis B e Antigen (HBeAg)-positive at Baseline | ||||||||||||||
End point description |
HBe seroconversion was defined as being both HBeAg-negative and Hepatitis B e antibody (HBeAb)-positive at Weeks 24, 48, and 96 in those subjects who had been HBeAg-positive at baseline. Method used was DiaSorin - Anti HBe enzyme immunoassay kit - procedure for qualitative determination of antibodies to HBeAg in human serum or plasma samples. Percentage was calculated using non-completer=failure, defined as number of subjects with HBe seroconversion at Weeks 24, 48, and 96 divided by the number of treated subjects who were HBeAg-positive at baseline. An exact binomial 95% confidence interval was constructed. Baseline was last measurement before or on Day 1 of study drug. All treated subjects who were HBeAg-positive at baseline were analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 24, 48, and 96
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Subjects With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 24, 48, 96 - Treated Population Who Were HBsAg-Positive at Baseline | ||||||||||||||
End point description |
Loss of HBsAg was defined as being HBsAg-negative at Weeks 24, 48, 96 in those subjects who had been HBsAg-positive at baseline. The method used: Immunoassay – ADVIA CENTAUR from SIEMENS: in vitro diagnostic immunoassay for the qualitative and quantitative determination of HBsAg in human serum and plasma (potassium ethylene diamine tetraacetic acid, lithium or sodium heparinized). Percentage was calculated using non-completer=failure, defined as number of subjects with a HBsAg loss at Weeks 24, 48, and 96 divided by the number of treated subjects who were HBsAg-positive at baseline (subjects were not enrolled into the study unless they were positive for HBsAg). An exact binomial 95% confidence interval was constructed. Baseline was last measurement before or on Day 1 of study drug. All treated subjects who were HBsAg-positive at baseline were analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 24, 48, 96
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Subjects With Hepatitis B Surface Antigen (HBsAg) Seroconversion at Weeks 24, 48, and 96 - Treated Population Who Were HBsAg-Positive at Baseline | ||||||||||||||
End point description |
HBsAg seroconversion was defined as being both HBsAg-negative and hepatitis B surface antibody (HBsAb)-positive at Weeks 24, 48, and 96 in those subjects who had been HBsAg-positive at baseline. The method used was an Immunoassay testing – ADVIA CENTAUR from SIEMENS: in vitro diagnostic immunoassay for the qualitative and quantitative determination of HBsAg in human serum and plasma [potassium ethylenediaminetetraacetic acid, lithium or sodium heparinized]. Percentage was calculated using non-completer=failure, defined as number of subjects with HBs seroconversion at Weeks 24 and 48 divided by the number of treated subjects who were HBsAg-positive at baseline. Positive result for HBsAg was one of the inclusion criteria. An exact binomial 95% confidence interval was constructed. Baseline was last measurement before or on Day 1 of study drug. All treated subjects who were HBsAg-positive at baseline were analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 24, 48, and 96
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of Subjects With Treatment Emergent Serious Adverse Events (SAEs) on Treatment, and Discontinuation of Study Drug Due to Adverse Events (AE) - Treated Population | ||||||||||
End point description |
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling. On-treatment = on Day 1 through last dose of study therapy + 5 days. All treated subjects were analyzed.
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End point type |
Secondary
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End point timeframe |
Day 1 to last dose of study drug plus 5 days; up to Week 96
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Subjects With Emergence of Genotypic Resistance to Study Drugs at Weeks 48 and 96 - Treated Population | ||||||||||
End point description |
Testing of Hepatitis B Virus (HBV) genotype was performed at baseline for all treated subjects and for subjects at Weeks 48 and 96 with primary non-response or virologic breakthrough. Emergent genotypic resistance to study drugs was defined as follows: Emergent=on-treatment substitution not present at baseline; entecavir resistance: subject’s sample had rtM204V/I/S and any substitution at rtT184, rtS202, or rtM250; tenofovir resistance: subject’s sample had rtA181T/V or rtN236T. Primary non-response was defined as <1 log10 decrease in HBV DNA from baseline on treatment at or after Week 12. Virologic breakthrough was defined as >=1 log10 increase in HBV DNA over nadir on treatment, either confirmed on treatment or last on-treatment followed by discontinuation of study therapy. n=number of subjects analyzed at Weeks 48 and 96.
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End point type |
Secondary
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End point timeframe |
Baseline to Weeks 48, 96
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| Notes [2] - Treated subjects who met resistance testing criteria; were tested for resistance to both drugs. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Subjects on Treatment With Study Drug With Laboratory Test Abnormalities Meeting Selected Criteria on Treatment - Treated Population | ||||||||||||||||||||||||||||||
End point description |
Select laboratory abnormalities and elevations on treatment are presented in each category. Baseline (BL); alanine transaminase (ALT); Creatinine (Cr) data presented below were confirmed, that is, at least 2 sequential measurement or last on-treatment measurement meeting the elevation criteria. On-treatment=after Day 1 through last dose of study therapy + 5 days. n=treated subjects with on-treatment laboratory test results.
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End point type |
Secondary
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End point timeframe |
Day 1 to last dose of study drug plus 5 days; up to Week 96
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| Notes [3] - Subjects who were evaluable for this end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 up to 96 Weeks
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Entecavir + Tenofovir
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Reporting group description |
Entecavir: Tablets, Oral, 1 mg, once daily, 96 weeks. Tenofovir disoproxil fumarate: Tablets, Oral, 300 mg, once daily, 96 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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22 Dec 2009 |
The purpose of this amendment was to provide protocol revisions in line with feedback received from the European Union Competent Authority and with the Summary of Product Characteristics for tenofovir. |
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18 Jan 2011 |
The purpose of this amendment was to: change the 24-hr Emergency Telephone Number; change the required number of enrolled and treated subjects, as well as the screening failure rate; replace, based on the current targeted number of treated subjects, the semi-width of the 95% confidence interval (CI) for a range of observed response rates, from 10% to 13.2%; change the number of subjects to be included in the interim analysis; clarify the sub-criteria for partial virological response; replace based on the current targeted number of treated subjects, the calculation of the 95% CI for the observed proportion from a 95% CI based on normal approximation into an exact binomial 95% CI; clarify the timing of the main (Week 48) and final (Week 96) analysis. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
