Clinical Trial Results:
A Phase I/II, Open-label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Etravirine (ETR) in Antiretroviral (ARV) Treatment-experienced HIV-1 Infected Infants and Children, Aged >= 2 Months to <6 Years
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Summary
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EudraCT number |
2012-002630-36 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
26 Aug 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
31 Mar 2021
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First version publication date |
31 Mar 2021
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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 |
TMC125-TIDP35-C234
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01504841 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Division of the National Institute of Allergy and Infectious Diseases (DAIDS)
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Sponsor organisation address |
5601 Fishers Lane, Rockville, United States,
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Public contact |
Clinical Registry Group, Janssen Research and Development, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Janssen Research and Development, ClinicalTrialsEU@its.jnj.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000222-PIP01-08 | ||
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 |
26 Aug 2020
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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 |
26 Aug 2020
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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 trial was to evaluate the steady-state pharmacokinetics (PK), safety and tolerability and appropriate dose of etravirine (ETR) in combination with an optimized background regimen (OBR) for human immunodeficiency virus (HIV)-1 infected children aged greater than or equal to (>=) 2 years to less than (<) 6 years.
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations were based upon adverse events (AEs) reported throughout the study, clinical laboratory test results, changes in physical examination including vital signs and electrocardiogram (ECGs) results.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Nov 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
5 Years | ||
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 |
Brazil: 9
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Country: Number of subjects enrolled |
United States: 4
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Country: Number of subjects enrolled |
South Africa: 13
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Worldwide total number of subjects |
26
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EEA total number of subjects |
0
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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) |
6
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Children (2-11 years) |
20
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 26 subjects were enrolled in the study and received at least 1 dose of etravirine (ETR). Out of those 26, 17 subjects completed the study. | ||||||||||||
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Pre-assignment
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Screening details |
3 sequential age cohorts were planned with 20 subjects in cohort 1, 6 subjects in cohort 2 and no enrollments occurred in cohort 3 during the study. | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Etravirine | ||||||||||||
Arm description |
Subjects were divided into 2 age-based cohorts: Cohort 1 (greater than or equal to [>=] 2 years to less than [<] 6 years age) and Cohort 2 (>= 1 year to <2 years age). Subjects received etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. ETR was administered as 25 milligrams (mg) scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Etravirine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Dispersible tablet
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Routes of administration |
Oral use
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Dosage and administration details |
ETR 25mg and/or 100mg was administered orally twice daily either swallowed as a whole tablet or dispersed in an appropriate liquid.
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Baseline characteristics reporting groups
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Reporting group title |
Etravirine
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Reporting group description |
Subjects were divided into 2 age-based cohorts: Cohort 1 (greater than or equal to [>=] 2 years to less than [<] 6 years age) and Cohort 2 (>= 1 year to <2 years age). Subjects received etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. ETR was administered as 25 milligrams (mg) scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Etravirine
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Reporting group description |
Subjects were divided into 2 age-based cohorts: Cohort 1 (greater than or equal to [>=] 2 years to less than [<] 6 years age) and Cohort 2 (>= 1 year to <2 years age). Subjects received etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. ETR was administered as 25 milligrams (mg) scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol. | ||
Subject analysis set title |
Cohort 1: >=2 to <6 years age
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug. ETR was administered as 25 mg scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol.
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Subject analysis set title |
Cohort 2: >=1 to <2 years age
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug. ETR was administered as 25 mg scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol.
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End point title |
Termination From Treatment due to a Suspected Adverse Drug Reaction (SADR) [1] | |||||||||
End point description |
An event judged to be at least possibly related to the study treatment was considered to be a SADR. Number of subjects who discontinued treatment due to a SADR by Cohort were reported. Intent to treat (ITT) population consisted of all subjects who had taken at least one dose of etravirine (ETR).
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End point type |
Primary
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End point timeframe |
Up to 5.77 years
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Subjects With Adverse Events of Grade 3 or Higher Severity [2] | |||||||||
End point description |
An AE is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Number of subjects with grade 3 or higher severity adverse events were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Primary
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End point timeframe |
Up to 5.77 years
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| Notes [2] - 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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Deaths [3] | |||||||||
End point description |
Number of deaths on study, by cohort were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Primary
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End point timeframe |
Up to 5.77 years
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| Notes [3] - 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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR [4] | ||||||||||||
End point description |
AUC12h was defined as area under curve from time of administration of ETR to 12 hours post dosing. AUC12h was determined at initial dose and recommended dose of ETR. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Primary
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End point timeframe |
Pre-dose, 1, 2, 4, 6, 9, and 12 hours post-dose measured at intensive PK visit (within 7-10 days after last dose of study drug administration)
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| Notes [4] - 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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects With Adverse Events of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications | |||||||||
End point description |
An AE is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Number of subjects with grade 3 or higher severity adverse events possibly related to study treatment were reported by cohort. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Secondary
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End point timeframe |
Up to 5.77 years
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Subjects With Confirmed Virologic Failure at Weeks 24 and 48 | |||||||||||||||
End point description |
Number of subjects with confirmed Virologic Failure, defined as: failure to suppress plasma human immunodeficiency virus (HIV)-1 ribosenucleic acid (RNA) to fewer than 400 copies per milliliter (copies/mL) and failure to achieve at least a 2-log10 reduction (from baseline) in HIV-1 RNA at Weeks 24 or 48, by Cohort, with Clopper-Pearson confidence intervals. The initial HIV-1 RNA results that met the Virologic Failure definition were each confirmed by a second result obtained within 1 to 4 weeks of the initial result obtained at Week 24 and/or 48. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Secondary
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End point timeframe |
Weeks 24 and 48
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Treatment Discontinued due to Toxicity or Virologic Failure | |||||||||
End point description |
Number of subjects who discontinued study treatment (ETR) due to a toxicity or Virologic Failure (VF), by cohort were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Secondary
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End point timeframe |
From baseline to occurrence of event, up to Week 48
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change in Optimized Background Regimen Due to Virologic Failure | |||||||||
End point description |
Number of subjects who initiated a change in their optimized background regimen (OBR) due to virologic failure, by Cohort were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Secondary
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End point timeframe |
Measured at entry and at Weeks 8, 12, 24, and 48
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| No statistical analyses for this end point | ||||||||||
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End point title |
New Onset Opportunistic Infection (OI) or AIDS Diagnosis | |||||||||
End point description |
Number of subjects with a new onset opportunistic infection (OI) or Acquired immunodeficiency syndrome (AIDS) diagnosis, by Cohort were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Secondary
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End point timeframe |
From baseline to occurrence of event, up to Week 48
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change from Baseline in CD4+ and CD8+ Cell Count | ||||||||||||||||||
End point description |
Change from baseline in cluster of differentiation (CD)4 and CD8 cell counts was reported to assess the immunologic change. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Secondary
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End point timeframe |
Every 12 Weeks from Baseline, up to 5.77 years or early discontinuation
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in CD4+ and CD8+ Cell Percentage | ||||||||||||||||||
End point description |
Change from baseline in CD4 and CD8 cell percentage was reported to assess the immunologic change. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Secondary
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End point timeframe |
Every 12 Weeks from Baseline, up to 5.77 years or early discontinuation
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in CD4/CD8 Ratio | ||||||||||||
End point description |
Change from baseline in CD4/CD8 count ratio was reported to assess the immunologic change. ITT population consisted of all subjects who had taken at least one dose of ETR.
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End point type |
Secondary
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End point timeframe |
Every 12 Weeks from Baseline, up to 5.77 years or early discontinuation
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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 |
Up to 5.77 years
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Adverse event reporting additional description |
Safety set included all subjects who have taken at least 1 dose of etravirine (ETR), regardless of their compliance with the protocol and adherence to the dosing regimen.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Etravirine
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Reporting group description |
Subjects were divided into 2 age-based cohorts: Cohort 1 (greater than or equal to [>=] 2 years to less than [<] 6 years age) and Cohort 2 (>= 1 year to <2 years age). Subjects received etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. ETR was administered as 25 milligrams (mg) scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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14 Dec 2012 |
The first amendment was issued to remove Cohorts IIB and IIIB (greater than or equal to [>=] 2-month to less than [<] 2-year old treatment-naive children, with or without exposure to antiretrovirals (ARVs) as part of a regimen to prevent mother-to-child transmission). Consequently, the number of
cohorts was changed from 5 to 3, the sample size was updated from 80 to 50 subjects, and stratification by ARV exposure was deleted. All sections throughout the protocol were updated accordingly, including the protocol title and study objectives. |
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04 Oct 2013 |
The second amendment was issued to revise the criteria for individual and cohort dose evaluations and adjustments.
Intensive pharmacokinetic (PK) sampling was to be performed on Day 14 (plus minus [+-] 4 days) of the study to allow etravirine (ETR) plasma concentrations to reach steady-state. In order to meet the PK criteria, at least 10 of 12 subjects per cohort were to have an area under plasma concentration-time curve over 12 hours of ETR (AUC12h) greater than (>) 2,350 nanograms * hour per milliliter (ng*h/mL) (>10th percentile of the adult AUC12h in the DUET studies) and a geometric mean AUC12h in the cohort to fall within 80 percent (%) to 130% of the geometric mean AUC12h in adults (that is, between 3,618 and 5,879 ng*h/mL). For individual PK-determined dose adjustments, a stepwise approach was introduced aimed at obtaining an ETR AUC12h around the 20th percentile of the adult AUC12h (instead of the median adult AUC12h) and with a first dose adjustment capped at 200 milligrams (mg) twice daily (bid). |
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05 Dec 2014 |
The third amendment was issued to incorporate revisions related to a change in the starting ETR dose (as per the new weight-banded ETR dosing table) for the study cohorts and a change in the overall PK criteria for evaluation of the (mini-)cohorts. Based on the high interindividual variability for apparent ETR clearance in the population PK model (62%), the target range for the geometric mean ETR AUC12h ratio (pediatric/adults) per age cohort was revised to be between 60% and 150% (instead of between 80% and 130%) of the geometric mean AUC12h in adults in the DUET studies (between 2,713 and 6,783 ng*h/mL). Since 2 subjects of the original mini-cohort already passed PK and safety criteria on the dose per amendment #2, and based on their body weight the same ETR dose would apply for them per amendment #3, it was agreed that these 2 subjects could be considered toward the new Cohort I minicohort under the amended protocol. Therefore, only 4 additional subjects needed to be enrolled to complete enrollment into that new mini-cohort. It was also agreed that subjects of the failed mini-cohort could be dose adjusted after an additional truncated intensive PK evaluation. The number of subjects to be enrolled was updated to account for the number of subjects needed to complete the dose-finding stage of the study and considering the number of subjects who were started on the final recommended ETR dose according to PK and safety criteria for that cohort. |
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10 Mar 2016 |
The fourth amendment was issued to revise the cohort management plan to allow early opening of the mini-cohort of Cohort III (while the first mini-cohort of Cohort II could still be enrolling) provided that the available Cohort II safety and PK were acceptable. Subjects <6 months of age could only be enrolled after initial safety and PK data from subjects between 6 months and 1 year of age were available. A go/no-go decision for further recruitment of study subjects was set approximately 2 years following the opening of Cohort II. At that time, an analysis was to be performed across all age cohorts (the Week-24 analysis). The accrual rate, and all relevant safety and PK data, were to be examined for determination of safety and value in continuing recruitment. |
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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 | |||
