Clinical Trial Results:
A Phase II, Open Label, Single Arm Trial to Evaluate the Pharmacokinetics, Safety, Tolerability, and Antiviral Activity of Rilpivirine (TMC278) in Antiretroviral-naïve HIV-1 Infected Adolescents and Children Aged >=6 to <18 Years
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Summary
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EudraCT number |
2008-001696-30 |
Trial protocol |
ES Outside EU/EEA |
Global end of trial date |
16 Aug 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Mar 2023
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First version publication date |
04 Mar 2023
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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 |
CR002677
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Janssen Research & Development LLC
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Sponsor organisation address |
920, US Highway, Route 202, South Raritan New Jersey, United States, 08869
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Public contact |
Clinical Registry Group, Janssen Research & Development LLC, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Janssen Research & Development LLC, 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-000317-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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Aug 2022
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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 |
16 Aug 2022
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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 (based on intensive pharmacokinetic analysis) of Rilpivirine 25 milligrams (mg) once daily (QD.) or adjusted dose of Rilpivirine QD in subjects aged greater than or equal to (>=) 12 to less than (<) 18 years and >=6 to <12 years and to evaluate safety and tolerability of Rilpivirine.
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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 Practice and applicable regulatory requirements.
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Background therapy |
Subjects received investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) (zidovudine [AZT], abacavir [ABC] or tenofovir disoproxil fumarate [TDF] in combination with lamivudine [3TC] or emtricitabine [FTC], in Cohort 1 (adolescents aged >=12 to <18 years) up to 240 weeks and in cohort 2 (children aged >=6 to <12 years) up to 48 Weeks. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Jan 2011
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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 |
56 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
India: 3
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Country: Number of subjects enrolled |
Thailand: 3
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Country: Number of subjects enrolled |
Uganda: 20
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Country: Number of subjects enrolled |
United States: 1
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Country: Number of subjects enrolled |
South Africa: 27
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Worldwide total number of subjects |
54
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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) |
0
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Children (2-11 years) |
18
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Adolescents (12-17 years) |
36
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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 |
- | ||||||||||||||
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Pre-assignment
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Screening details |
A total of 54 antiretroviral-naïve human Immunodeficiency Virus-1 (HIV-1) infected adolescents and children participants were enrolled and treated. | ||||||||||||||
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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 |
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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Cohort 1 and 2: Rilpivirine: All Subjects | ||||||||||||||
Arm description |
Cohort 1 (adolescents aged greater than or equal to [>=] 12 to less than [<] 18 years), subjects received rilpivirine tablet 25 milligrams (mg) or adjusted dose orally once daily (QD) up to 240 weeks. In Cohort 2 (children aged >=6 to <12 years), received rilpivirine body weight adjusted dose (body weight <20 kilograms [kg]: 12.5 mg; between 20 kg to <25kg: 15 mg; >=25 kg: 25 mg) orally QD up to 48 weeks. In both the cohorts, rilpivirine was administered in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) oremtricitabine (FTC). | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Rilpivirine
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Investigational medicinal product code |
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Other name |
TMC278
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Cohort 1: Rilpivirine 25 mg QD for 240 weeks and Cohort 2: weight adjusted dose (<20 kg: 12.5 mg; 20 kg to <25 kg: 15 mg; >=25 kg: 25 mg) QD for 48 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Cohort 1 and 2: Rilpivirine: All Subjects
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Reporting group description |
Cohort 1 (adolescents aged greater than or equal to [>=] 12 to less than [<] 18 years), subjects received rilpivirine tablet 25 milligrams (mg) or adjusted dose orally once daily (QD) up to 240 weeks. In Cohort 2 (children aged >=6 to <12 years), received rilpivirine body weight adjusted dose (body weight <20 kilograms [kg]: 12.5 mg; between 20 kg to <25kg: 15 mg; >=25 kg: 25 mg) orally QD up to 48 weeks. In both the cohorts, rilpivirine was administered in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) oremtricitabine (FTC). | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort 1 and 2: Rilpivirine: All Subjects
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Reporting group description |
Cohort 1 (adolescents aged greater than or equal to [>=] 12 to less than [<] 18 years), subjects received rilpivirine tablet 25 milligrams (mg) or adjusted dose orally once daily (QD) up to 240 weeks. In Cohort 2 (children aged >=6 to <12 years), received rilpivirine body weight adjusted dose (body weight <20 kilograms [kg]: 12.5 mg; between 20 kg to <25kg: 15 mg; >=25 kg: 25 mg) orally QD up to 48 weeks. In both the cohorts, rilpivirine was administered in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) oremtricitabine (FTC). | ||
Subject analysis set title |
Cohort 1 (>=12 to <18 Years): Rilpivirine
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects received rilpivirine tablet 25 mg or adjusted dose orally QD up to 240 weeks in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) oremtricitabine (FTC).
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Subject analysis set title |
Cohort 2 (>=6 to <12 Years): Rilpivirine
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects received rilpivirine tablet 25 mg or adjusted dose orally QD up to 240 weeks up to protocol amendment 9, up to 48 weeks from protocol amendment 10, in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) or emtricitabine (FTC).
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Subject analysis set title |
Cohort 2 (>=10 to <20 kg): Rilpivirine 12.5 mg QD
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
In Cohort 2 (children aged >=6 to <12 years), subjects received body weight adjusted dose of Rilpivirine 12.5 mg orally QD (for subjects with body weight >=10 to <20 kg) up to 48 weeks. In both the cohorts, rilpivirine was administered in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) or emtricitabine (FTC).
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Subject analysis set title |
Cohort 2 (>=20 to <25 kg): Rilpivirine 15 mg
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
In Cohort 2 (children aged >=6 to <12 years), subjects received body weight adjusted dose of Rilpivirine 15 mg orally QD (for subjects with body weight >=20 to <25 kg) up to 48 weeks. In both the cohorts, rilpivirine was administered in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) or emtricitabine (FTC).
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Subject analysis set title |
Cohort 2 (>=20 to <25 kg): Rilpivirine 25 mg
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
In Cohort 2 (children aged >=6 to <12 years), subjects received body weight adjusted dose of Rilpivirine 25 mg orally QD (for subjects with body weight >=20 to <25 kg) up to 48 weeks. In both the cohorts, rilpivirine was administered in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) or emtricitabine (FTC).
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Subject analysis set title |
Cohort 2 (>=25 kg): Rilpivirine 25 mg
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
In Cohort 2 (children aged >=6 to <12 years), subjects received body weight adjusted dose of Rilpivirine 25 mg orally QD (for subjects with body weight >=25 kg) up to 48 weeks. In both the cohorts, rilpivirine was administered in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) or emtricitabine (FTC).
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End point title |
Pharmacokinetics (PK) of Rilpivirine (TMC278) as Measured by Maximum Plasma Concentration (Cmax) [1] | ||||||||||||||||||||||||
End point description |
Cmax is the maximum plasma concentration. Analysis population included all subjects who had taken at least 1 dose of rilpivirine, regardless of their compliance with the protocol and adherence to the dosing regimen. Here, N (number of subjects analysed) signifies subjects evaluated for this endpoint. "99999" indicated that mean and SD could not be calculated because number analysed was <3.
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End point type |
Primary
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End point timeframe |
Up to Week 4
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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: 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 |
Pharmacokinetics of Rilpivirine as Measured by Area Under the Plasma Concentration Curve (AUC24) [2] | ||||||||||||||||||||||||
End point description |
AUC24 was defined area under the plasma concentration versus time curve from time 0 to 24 hours post dosing of rilpivirine. Analysis population included all subjects who had taken at least 1 dose of RPV, regardless of their compliance with the protocol and adherence to the dosing regimen. Here, N (number of subjects analysed) signifies subjects evaluated for this endpoint. "99999" indicated that mean and SD could not be calculated because number analysed was <3.
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End point type |
Primary
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End point timeframe |
Up to Week 4
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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 |
Percentage of Subjects With Plasma Human Immunodeficiency Virus -1 (HIV-1) Ribonucleic Acid (RNA) level Less Than (<) 50 Copies/mL | ||||||||||||||||||
End point description |
Time to loss of virologic response algorithm (TLOVR) requires sustainedHIV-1 RNA < 50 copies/mL; confirmed HIV-1 RNA more than or equal to (>=) 50 copies/mL is considered as non-response (rebound); subject was considered non-responder after permanent discontinuation. Responder is defined as the subject with confirmed plasma viral load <50 copies/mL. Analysis population included all subjects who had taken at least 1 dose of RPV, regardless of their compliance with the protocol and adherence to the dosing regimen. "99999" indicated that data was not collected at Week 240 for Cohort 2. "9999" indicated that data was not collected at Week 48 for Cohort 2 as planned. Here, 'n' (number analysed) signifies number of subjects with available data at each specified timepoint.
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End point type |
Secondary
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End point timeframe |
Weeks 48 and 240
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Subjects with Adverse Events (AEs) | |||||||||
End point description |
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal (investigational or non-investigational) product and did not necessarily have a causal relationship with the treatment. Analysis population included all subjects who had taken at least 1 dose of RPV, regardless of their compliance with the protocol and adherence to the dosing regimen. This endpoint was planned to be reported for Cohort 1 only.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) up to Week 48 for Cohort 2 and up to Week 240 for Cohort 1
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Subjects With Post Baseline Genotype Data | ||||||||||||||||||
End point description |
Number of subjects with post baseline genotype (nucleoside analogue reverse transcriptase inhibitors [NRTI] and non-nucleoside reverse transcriptase inhibitors [NNRTI] resistance) data were reported. Analysis population included all subjects who had taken at least 1 dose of RPV, regardless of their compliance with the protocol and adherence to the dosing regimen. Here, N (Number of subjects analysed) signifies subjects evaluated for this endpoint.
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End point type |
Secondary
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End point timeframe |
Cohort 2: up to 48 weeks and Cohort 1: up to 240 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage of Subjects with Plasma HIV-1 RNA <50 Copies/mL by Food and Drug Administration (FDA) Snapshot Approach | ||||||||||||||||||
End point description |
Percentage of subjects with a HIV-1 RNA <50 copies per mL were assessed using FDA snapshot approach which defines a participant's virologic response status using only the viral load at the predefined time point within a window of time, along with study drug discontinuation status. If HIV-1 RNA level is < 50 copies per mL, it is considered as virologic success as per the snapshot approach. Analysis population included all subjects who had taken at least 1 dose of RPV, regardless of their compliance with the protocol and adherence to the dosing regimen. Here, 'n' (number analysed) signifies number of subjects with available data at each specified timepoint. "99999" indicated that data was not collected at Week 240 for Cohort 2 arm because Cohort 2 duration was up to Week 48 only.
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End point type |
Secondary
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End point timeframe |
At Week 48 (for Cohorts 1 and 2) and at Week 240 (for Cohort 1 only)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline in Cluster of Differentiation (CD4+) Cells | ||||||||||||||||||
End point description |
The immunologic change was determined by changes in Cluster of CD4+ cell count using non-completer =failure imputation, that is discontinuation were imputed with baseline value resulting in change=0, other missing data using last observation carried forward (LOCF). Change from baseline in CD4+ cell count at Week 48 for Cohort 1 and 2 and Week 240 for Cohort 1 only were assessed. Analysis population included all subjects who had taken at least 1 dose of RPV, regardless of their compliance with the protocol and adherence to the dosing regimen. Here, 'n' (number analysed) signifies number of subjects with available data at each specified timepoint. 99999 indicated that data was not collected at Week 240 for Cohort 1 arm as analysis was not planned to be collected at Week 240 for this arm.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 48 for Cohort 1 and 2; Week 240 for Cohort 1 only
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage of Subjects With Treatment Adherence >95% Based on Drug Accountability | ||||||||||||||||||
End point description |
Percentage of subjects with treatment adherence >95% based on drug accountability up to 48 Weeks for Cohort 2 and up to 240 Weeks Cohort 1 were reported. Treatment adherence was defined as having a treatment adherence of greater than (>) 95 percent (%) by pill count. Analysis population included all subjects who had taken at least 1 dose of RPV, regardless of their compliance with the protocol and adherence to the dosing regimen.
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End point type |
Secondary
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End point timeframe |
Up to 48 Weeks for Cohort 2 and up to 240 Weeks Cohort 1
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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 |
From Baseline (Day 1) up to 48 weeks for Cohort 2; From Baseline (Day 1) up to 240 weeks for Cohort 1
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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 |
24.0
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Reporting groups
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Reporting group title |
Cohort 1 and 2: Rilpivirine: All Subjects
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Reporting group description |
Cohort 1 (adolescents aged greater than or equal to [>=] 12 to less than [<] 18 years), subjects received rilpivirine tablet 25 milligrams (mg) or adjusted dose orally once daily (QD) up to 240 weeks. In Cohort 2 (children aged >=6 to <12 years), received rilpivirine body weight adjusted dose (body weight <20 kilograms [kg]: 12.5 mg; between 20 kg to <25kg: 15 mg; >=25 kg: 25 mg) orally QD up to 48 weeks. In both the cohorts, rilpivirine was administered in combination with an investigator-selected background regimen containing 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs): zidovudine (AZT), abacavir (ABC), or tenofovir disoproxil fumarate (TDF) in combination with lamivudine (3TC) oremtricitabine (FTC). | ||||||||||||||||||||||||||||||
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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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05 Aug 2009 |
The overall reasons for the amendment were the addition of an optional post-Week 48 treatment extension period of 4 years, changes in withdrawal, in- and exclusion criteria and additional assessments of several hormones and CD4+ cell count. |
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20 May 2010 |
The overall reason for the amendment was to allow subjects to switch to a weight-adjusted dose, if needed, and to allow TDF and FTC as investigator-selected background regimen. |
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29 Jun 2011 |
The overall reasons for the amendment was the addition of Part 1b before starting Part 2 of the study and the provision of the post-Week 48 treatment extension period of 4 years through the trial and not via a specific roll-over trial. |
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08 Oct 2015 |
The overall reason for the amendment was to also include children of >=6 to <12 years of age. |
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18 Dec 2015 |
The overall reason for the amendment was the update of inclusion criterion 3 to remove the requirement that children enrolled in the study were aware of their human immunodeficiency virus (HIV) status, so that children that are unaware of their HIV status, but comply with all other inclusion and exclusion criteria were allowed to participate in the study. |
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01 Dec 2016 |
The overall reason for the amendment were adjustments made to allow the prescription of World Health Organization (WHO) prequalified drugs, based on local practice and availability of anti-retrovirals (ARV)s. If not available, the use of generic drugs approved by the local Health Authorities or drugs prescribed by the United Nations international organizations can be acceptable as N(t)RTI background medication. Additionally, the criterion for withdrawal after a total cumulative duration of treatment interruptions for suspected toxicities was further clarified per study period instead of over the entire study duration. |
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20 Mar 2018 |
The overall reason for the amendment was to update the inclusion and exclusion criteria to facilitate subject recruitment since the study target population had become scarce. Through this amendment, enrollment of subjects >=6 to <12 years of age who had a history of receiving a single dose nevirapine for prevention of prevention of mother-to-child transmission (PMTCT) in Cohort 2 of the study was allowed. The evolution of proviral genotype was assessed at screening and Week 48 and virologic response was closely monitored during the treatment period. |
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03 Feb 2020 |
The overall reason for the amendment was to include Rilpivirine dose recommendations for subjects in Cohort 2 with a body weight >=25 kg (25 mg QD) and <25 kg (15 mg QD). Based on accumulating data the new dose of 15 mg QD had been selected for the subgroup of participants with a body weight <25 kg. Since for subjects with body weight >=25 kg, sufficient intensive pharmacokinetic (PK) data had been gathered, this amendment also included intensive PK evaluation in newly enrolled subjects with a body weight <25 kg to further evaluate and confirm the Rilpivirine dose for participants with this lower body weight. |
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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 | |||
