Safety and Efficacy of Adefovir Dipivoxil in Children and Adolescents With Chronic Hepatitis B

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Gilead Sciences

ClinicalTrials.gov Identifier:

NCT00095121

First received: October 29, 2004

Last updated: May 16, 2012

Last verified: May 2012

History of Changes

Results First Received: April 8, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator); Primary Purpose: Treatment
Condition:	Chronic Hepatitis B
Interventions:	Drug: Placebo (PLB) Drug: Adefovir Dipivoxil (ADV) Drug: Lamivudine

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
First participant screened on 17 May 2004; first participant randomized on 21 June 2004. Participants from Gilead pharmacokinetics Study GS-02-517 were allowed to enroll regardless of screening serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) or alanine aminotransferase (ALT) concentration if they met all other entry criteria.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
ADV - ADV	Once daily treatment: children aged 2 to <7 years received 0.3 mg/kg oral suspension; children aged >=7 to <12 years received 0.25 mg/kg oral suspension; children aged >=12 to <18 years received 10 mg tablet. The adefovir dipivoxil (ADV) baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind [DB] ADV [ADV-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240). Lamivudine was to be added to the open-label ADV regimen of subjects between 12 and <18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration >= 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.
PLB - ADV	Placebo (PLB) was matched to adefovir dipivoxil treatment (oral suspension or tablet) by age group. The ADV baseline was defined as the day of first dose of ADV (ie, Week 48 for those originally randomized to placebo [PLB-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the PLB-ADV group could receive only up to 192 weeks of open-label (OL) ADV treatment (ADV Week 192). Lamivudine was to be added to the open-label ADV regimen of subjects between 12 and <18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration >= 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.

Description

ADV - ADV

Once daily treatment: children aged 2 to <7 years received 0.3 mg/kg oral suspension; children aged >=7 to <12 years received 0.25 mg/kg oral suspension; children aged >=12 to <18 years received 10 mg tablet. The adefovir dipivoxil (ADV) baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind [DB] ADV [ADV-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240). Lamivudine was to be added to the open-label ADV regimen of subjects between 12 and <18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration >= 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.

PLB - ADV

Placebo (PLB) was matched to adefovir dipivoxil treatment (oral suspension or tablet) by age group. The ADV baseline was defined as the day of first dose of ADV (ie, Week 48 for those originally randomized to placebo [PLB-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the PLB-ADV group could receive only up to 192 weeks of open-label (OL) ADV treatment (ADV Week 192). Lamivudine was to be added to the open-label ADV regimen of subjects between 12 and <18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration >= 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.

Participant Flow for 2 periods

Period 1: Double-Blind (Study Weeks 0 Through 48)

	ADV - ADV	PLB - ADV
STARTED	115	58
COMPLETED	112	58
NOT COMPLETED	3	0
Adverse Event	1	0
Not Compliant	2	0

Period 2: Open-Label (Study Weeks 49 Through 240)

	ADV - ADV	PLB - ADV
STARTED	108	54
Received Lamivudine (LAM) After Week 96	21	11
COMPLETED	46 ^[1]	35 ^[1]
NOT COMPLETED	62	19

[1]	Completed the 240-week study period either on or off treatment at Week 240.

Baseline Characteristics

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Reporting Groups

	Description
ADV - ADV	Once daily treatment: children aged 2 to <7 years received 0.3 mg/kg oral suspension; children aged >=7 to <12 years received 0.25 mg/kg oral suspension; children aged >=12 to <18 years received 10 mg tablet. The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to DB ADV [ADV-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240).
PLB - ADV	Placebo was matched to adefovir dipivoxil treatment (oral suspension or tablet) by age group. The ADV baseline was defined as the day of first dose of ADV (ie, Week 48 for those originally randomized to placebo [PLB-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192).
Total	Total of all reporting groups

Baseline Measures

	ADV - ADV	PLB - ADV	Total
Number of Participants [units: participants]	115	58	173
Age [units: participants]
<=18 years	115	58	173
Between 18 and 65 years	0	0	0
>=65 years	0	0	0
Age [units: years] Mean ± Standard Deviation	10.8 ± 4.33	10.7 ± 3.94	10.8 ± 4.19
Gender [units: participants]
Female	41	19	60
Male	74	39	113
Ethnicity (NIH/OMB) [units: participants]
Hispanic or Latino	1	0	1
Not Hispanic or Latino	114	58	172
Unknown or Not Reported	0	0	0
Race (NIH/OMB) [units: participants]
American Indian or Alaska Native	1	0	1
Asian	29	12	41
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	11	3	14
White	70	41	111
More than one race	4	2	6
Unknown or Not Reported	0	0	0
Region of Enrollment [units: participants]
United States	35	13	48
Belgium	6	3	9
Germany	11	8	19
Poland	48	27	75
Spain	4	4	8
United Kingdom	11	3	14
Body Mass Index (Males) [units: kg/cm^2] Mean ± Standard Deviation	19.3 ± 4.04	19.7 ± 4.87	19.4 ± 4.33
Body Mass Index (Females) [units: kg/cm^2] Mean ± Standard Deviation	17.8 ± 3.68	17.7 ± 3.76	17.7 ± 3.67
Prior Exposure to Hepatitis B Treatment [units: participants]
Yes	64	33	97
No	51	25	76
HBV DNA [units: log10 copies/mL] Mean ± Standard Deviation	8.74 ± 0.894	8.67 ± 1.016	8.71 ± 0.935
Hepatitis B Surface Antigen (HBsAg) [units: participants]
Negative	0	0	0
Positive	115	58	173
Antibody to HBsAg (HBsAb) [units: participants]
Negative	0	0	0
Positive	0	0	0
Not Done	115	58	173
Hepatitis B e Antigen (HBeAg) [units: participants]
Negative	2	1	3
Positive	113	57	170
Antibody to HBeAg (HBeAb) [units: participants]
Negative	0	0	0
Positive	2	1	3
Not Done	113	57	170
ALT [units: U/L] Mean ± Standard Deviation	111 ± 81.6	99 ± 52.8	107 ± 73.3
ALT [units: participants]
>= Upper Limit of Normal (ULN)	108	56	164
<ULN	7	2	9
ALT as Multiple of ULN [units: participants]
<=median (2.265)	57	30	87
>median (2.265)	58	28	86
ALT Category [units: participants]
Alanine aminotransferase <=ULN	8	2	10
ULN <alanine aminotransferase <=2*ULN	37	25	62
2ULN <alanine aminotransferase <=5ULN	52	26	78
Alanine aminotransferase >5*ULN	18	5	23
ALT (Multiples of ULN) [units: multiples] Mean ± Standard Deviation	2.9 ± 2.03	2.6 ± 1.40	2.8 ± 1.85
Genotype ^[1] [units: participants]
HBV Genotype A	51	32	83
HBV Genotype B	13	5	18
HBV Genotype C	10	4	14
HBV Genotype D	35	14	49
HBV Genotype E	3	2	5
HBV Genotype F	2	0	2
Not Done	1	1	2
Time Since HBV Diagnosis [units: years until enrollment] Mean ± Standard Deviation	6.8 ± 4.12	6.8 ± 4.06	6.8 ± 4.09
Mode of HBV Acquisition [units: participants]
Perinatal transmission or within 1st year of life	47	24	71
Unknown	37	21	58
Childhood acquisition after 1st year of life	19	8	27
Transfusion or exposure to infected blood products	8	3	11
Other	4	2	6
Intravenous drug user	0	0	0
Missing	0	0	0
Sexual contact with HBV infected person	0	0	0
Symptoms of Acute Hepatitis B ^[2] [units: participants]
Yes	2	2	4
No	113	56	169
Hepatitis B Flares (Acute Exacerbation) ^[3] [units: participants]
Yes	12	4	16
No	103	54	157
Current Alcohol Consumption [units: participants]
Yes	0	0	0
No	115	58	173
Any Prior Hepatitis B Medication [units: participants]
Yes	66	33	99
No	49	25	74
Prior Use of Famciclovir [units: participants]
Yes	0	1	1
No	115	57	172
Prior Use of Lamivudine [units: participants]
Yes	46	23	69
No	69	35	104
Prior Use of Interferon Alpha [units: participants]
Yes	52	28	80
No	63	30	93
Prior Use of ADV [units: participants]
Yes	4	4	8
No	111	54	165
Prior Use of Other Hepatitis B Medications ^[4] [units: participants]
Yes	8	2	10
No	107	56	163

[1]	Identification of specific HBV genotype (ie, Genotype A, B, C, D, E, or F).
[2]	Symptoms of acute HBV infection include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, clay-colored bowel movements, joint pain, and jaundice. - cdc.gov [homepage on the Internet]. Atlanta: Centers for Disease Control and Prevention. Hepatitis B Information for Health Professionals; [updated 2011 April 4]. Available from: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm.
[3]	A hepatic flare was defined as a) serum ALT > 2 x study baseline and > 10 x ULN or b) an ALT 1-grade shift or ALT 2 x previous value and total bilirubin > 2.5 mg/dL or change from study baseline in total bilirubin = 1.0 mg/dL or change from study baseline in prothrombin time > 2 seconds or serum albumin < 3.0 g/dL or change from study baseline in serum albumin <= −1.0 g/dL.
[4]	"Other hepatitis B medications" include any medications other than famciclovir, lamivudine, lobucavir, thymosin alpha, ganciclovir, interferon alpha, hepatitis B immune globulin (HBIG), entecavir, clevudine, emtricitabine, and ADV.

Outcome Measures

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1. Primary:

Percentage of Participants With Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < 1000 Copies/mL (Polymerase Chain Reaction [PCR]-Based Assay) and Normal Alanine Aminotransferase (ALT) at Week 48 (Missing = Failure) [ Time Frame: Week 48 ]

Show Outcome Measure 1

2. Secondary:

Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline) [ Time Frame: ADV baseline ]

Show Outcome Measure 2

3. Secondary:

Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment - Missing = Failure) (ADV Week 192) [ Time Frame: ADV Week 192 ]

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4. Secondary:

Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240) [ Time Frame: ADV Week 240 ]

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5. Secondary:

Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline) [ Time Frame: ADV baseline ]

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6. Secondary:

Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 192) [ Time Frame: ADV Week 192 ]

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Measure Type	Secondary
Measure Title	Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 192)
Measure Description	Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192).
Time Frame	ADV Week 192
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded.

Reporting Groups

Description

ADV - ADV

PLB - ADV

Placebo was matched to adefovir dipivoxil treatment (oral suspension or tablet) by age group. The ADV baseline was defined as the day of first dose of ADV (ie, Week 48 for those originally randomized to placebo [PLB-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192).

Measured Values

	ADV - ADV	PLB - ADV
Number of Participants Analyzed [units: participants]	108	54
Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 192) [units: percentage of participants]	11	13

No statistical analysis provided for Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 192)

7. Secondary:

Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240) [ Time Frame: ADV Week 240 ]

Show Outcome Measure 7

8. Secondary:

Adefovir (ADV) Baseline Serum HBV DNA [ Time Frame: ADV baseline ]

Show Outcome Measure 8

9. Secondary:

Change From ADV Baseline to ADV Week 192 for Serum HBV DNA [ Time Frame: ADV baseline to ADV 192 weeks ]

Show Outcome Measure 9

10. Secondary:

Change From ADV Baseline to ADV Week 240 for Serum HBV DNA [ Time Frame: ADV baseline to ADV 240 weeks ]

Show Outcome Measure 10

11. Secondary:

ADV Baseline ALT [ Time Frame: ADV baseline ]

Show Outcome Measure 11

12. Secondary:

Change From ADV Baseline to ADV Week 192 for ALT [ Time Frame: ADV baseline to ADV 192 weeks ]

Show Outcome Measure 12

13. Secondary:

Change From ADV Baseline to ADV Week 240 for ALT [ Time Frame: ADV baseline to ADV 240 weeks ]

Show Outcome Measure 13

14. Secondary:

Percentage of Participants With Normal ALT at Adefovir Baseline (Missing = Failure) [ Time Frame: ADV baseline ]

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15. Secondary:

Percentage of Participants With Normal ALT at ADV Week 192 (Missing = Failure) [ Time Frame: ADV Week 192 ]

Show Outcome Measure 15

16. Secondary:

Percentage of Participants With Normal ALT at ADV Week 240 (Missing = Failure) [ Time Frame: ADV Week 240 ]

Show Outcome Measure 16

17. Secondary:

Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss or Seroconversion by End of Blinded Treatment (Study Week 48; Randomized and Treated Analysis Set) [ Time Frame: Study Week 0 to Study Week 48 (double-blind period) ]

Show Outcome Measure 17

18. Secondary:

Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 192 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded) [ Time Frame: ADV baseline to ADV Week 192 ]

Show Outcome Measure 18

19. Secondary:

Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 240 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded) [ Time Frame: ADV baseline to ADV Week 240 ]

Show Outcome Measure 19

20. Secondary:

Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) [ Time Frame: 240 weeks ]

Show Outcome Measure 20

21. Secondary:

Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) for Subjects Who Received Combination ADV + Lamivudine Therapy [ Time Frame: 240 weeks ]

Show Outcome Measure 21

22. Secondary:

Percentage of Participants With Durable HBeAg Seroconversion [ Time Frame: 240 weeks ]

Show Outcome Measure 22

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Publication must include results in their entirety and not as individual center data. Results may be published/presented at scientific meetings. All manuscripts/abstracts must be submitted to Gilead prior to submission. Any formal publication of the study in which input of Gilead personnel exceeded that of conventional monitoring will be considered as a joint publication by the investigator and the appropriate Gilead personnel.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: John Flaherty, PharmD, Director, Clinical Research
Organization: Gilead Sciences
phone: 650-522-5592
e-mail: John.Flaherty@gilead.com

Publications:

Sokal, E, Kelly, D, et al. The Pharmacokinetics (PK) and Safety of a Single Dose of Adefovir Dipivoxil (ADV) in Children and Adolescents (Aged 2-17) with Chronic Hepatitis B. JHepatol,Vol 40(Suppl 1), P. 132, 2004.

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT00095121 History of Changes
Other Study ID Numbers:	GS-US-103-0518
Study First Received:	October 29, 2004
Results First Received:	April 8, 2011
Last Updated:	May 16, 2012
Health Authority:	United States: Food and Drug Administration

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