Human Immunodeficiency Virus 1
Conditions
Keywords
Human immunodeficiency virus 1, HIV-1, Darunavir, Ritonavir, Norvir
Brief summary
The purpose of this study is to evaluate the pharmacokinetics (what the body does to the medication), safety and antiviral activity to support dose recommendations by body weight of darunavir with low-dose ritonavir (DRV/rtv), in combination with other antiretroviral drugs (ARVs), in treatment-experienced Human immunodeficiency virus 1 (HIV 1) infected children.
Detailed description
This is an open-label (all people know the identity of the intervention), study to evaluate the pharmacokinetics, safety and antiviral activity. Approximately 24 HIV-1 infected children will be enrolled in this study. The study consists of a 4-week screening period, a 48-week treatment period, and a 4-week follow-up period. Participants will receive DRV/rtv according to their body weight. Safety evaluations will include assessment of adverse events, laboratory tests, physical Examination, neurologic examination, vital signs, and electrocardiogram. The total duration of the study will be 56 weeks.
Interventions
DRUGDarunavir
Darunavir oral suspension (100 mg/mL) will be administered as 20 mg per kg body weight twice daily for children weighing between 10 and \<20 kg before dose adjustment. Darunavir oral suspension will be administered 25 mg per kg body weight twice daily if weight less than 15 kg, and fixed dose of 375 mg darunavir tablets twice daily if weight more than or equal to 15 kg after dose adjustment.
DRUGRitonavir
Ritonavir oral solution (80 mg/mL) will be administered as 3 mg per kg body weight twice daily before dose adjustment and after dose adjustment fixed dose of 50 mg twice daily if weight more than or equal to 15 kg.
Sponsors
Tibotec Pharmaceutical Limited
Tibotec Pharmaceuticals, Ireland
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 6 Years
Healthy volunteers
No
Inclusion criteria
* Participants with a documented HIV 1 infection (by any of the local standard diagnostic methods, such as HIV PCR-DNA, ELISA or western blot (WB) test for HIV antibodies, etc.) * Body weight from 10 kg to less than 20 kg at screening * Participants currently on stable ART (anti retroviral therapy) for at least 12 weeks, who need to change their ARV regimen because it is currently failing, with a viral load of greater than 1000 copies/mL * Screening genotype resistance test results showing less than 3 DRV resistance-associated mutations * Parents or legal representative willing and able to give consent
Exclusion criteria
* Participants with presence of any currently active conditions included in the listing of WHO ( World Health Organisation) Clinical Stage 4 and participants with presence of a non-HIV encephalopathy * Administration of any ARV (antiretroviral) or non-ARV investigational medication or investigational vaccine within 30 days prior to screening, except for those medications where dose recommendations for children are available * Life expectancy less than 6 months, according to the judgment of the investigator * Co-enrollment in other clinical and/or cohort trials without written permission of the Sponsor * Participants with any active clinically significant disease (eg, tuberculosis \[TB\], cardiac dysfunction, pancreatitis, acute viral infections) or findings during screening of medical history or physical examination that, in the investigator's opinion, would compromise the subject's safety or outcome of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Virological Response (Viral Load Less Than 50 Copies/mL) at Week 24 - Time to Loss of Virologic Response (TLOVR) | Week 24 | The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders after discontinuation. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With Virological Response (Viral Load Less Than 50 Copies/mL) at Week 48 | Week 48 |
| Number of Participants With Virological Response (Viral Load Less Than 400 Copies/mL) at Week 24 and Week 48 | Week 24 and Week 48 |
| Number of Participants With Less Than or Equal to 1 log10 Decrease in Plasma Viral Load at Week 24 and Week 48 | Week 24 and Week 48 |
| Mean Change From Baseline to Week 24 and Week 48 in Plasma log10 Viral Load | Baseline, Week 24 and Week 48 |
| Mean Change From Baseline to Week 24 and Week 48 in CD4+ Percentage | Baseline, Week 24 and Week 48 |
Countries
Argentina, Brazil, India, Kenya, South Africa
Participant flow
Recruitment details
This study was conducted in 5 countries: Argentina, Brazil, India, Kenya, and South Africa.
Pre-assignment details
27 participants were recruited and treated in this study; as Good Clinical Practice (GCP) requirements were not consistently adhered to at one site (involving 6 participants), analyses were performed excluding the participants from this site, resulting in 21 participants used for analyses.
Participants by arm
| Arm | Count |
|---|---|
| DRV/Rtv Before dose adjustment, oral darunavir suspension (100 mg/mL): 20 mg per kg body weight twice daily for children weighing between 10 and \<20 kg. After dose adjustment, 25 mg per kg body weight twice daily if weight less than 15 kg, and fixed dose of 375 mg twice daily if weight more than or equal to 15 kg. Before dose adjustment, oral ritonavir solution (80 mg/mL): 3 mg per kg body weight twice daily and after dose adjustment fixed dose of 50 mg twice daily if weight more than or equal to 15 kg | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | DRV/Rtv |
|---|---|
| Age, Continuous | 4.6 years FULL_RANGE 0.89 |
| Body Mass Index (BMI) | 15.1 kg/m^2 STANDARD_DEVIATION 1.51 |
| Region of Enrollment Argentina | 4 participants |
| Region of Enrollment Brazil | 6 participants |
| Region of Enrollment India | 1 participants |
| Region of Enrollment South Africa | 10 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 21 |
| serious Total, serious adverse events | 2 / 21 |
Outcome results
Primary
Number of Participants With Virological Response (Viral Load Less Than 50 Copies/mL) at Week 24 - Time to Loss of Virologic Response (TLOVR)
The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders after discontinuation. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm.
Time frame: Week 24
Population: 27 participants were recruited and received at least 1 dose of study medication; as Good Clinical Practice (GCP) requirements were not consistently adhered to at one site (involving 6 participant), analyses were performed excluding the participants from this site, resulting in 21 participants used for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DRV/Rtv | Number of Participants With Virological Response (Viral Load Less Than 50 Copies/mL) at Week 24 - Time to Loss of Virologic Response (TLOVR) | 13 Participants |
Secondary
Mean Change From Baseline to Week 24 and Week 48 in CD4+ Percentage
Time frame: Baseline, Week 24 and Week 48
Population: 27 participants were recruited and received at least 1 dose of study medication; as Good Clinical Practice (GCP) requirements were not consistently adhered to at one site (involving 6 participant), analyses were performed excluding the participants from this site, resulting in 21 participants used for analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DRV/Rtv | Mean Change From Baseline to Week 24 and Week 48 in CD4+ Percentage | Week 24 | 4 Percentage of lymphocytes | Standard Error 0.9 |
| DRV/Rtv | Mean Change From Baseline to Week 24 and Week 48 in CD4+ Percentage | Week 48 | 4 Percentage of lymphocytes | Standard Error 1.3 |
Secondary
Mean Change From Baseline to Week 24 and Week 48 in Plasma log10 Viral Load
Time frame: Baseline, Week 24 and Week 48
Population: 27 participants were recruited and received at least 1 dose of study medication; as Good Clinical Practice (GCP) requirements were not consistently adhered to at one site (involving 6 participant), analyses were performed excluding the participants from this site, resulting in 21 participants used for analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DRV/Rtv | Mean Change From Baseline to Week 24 and Week 48 in Plasma log10 Viral Load | Week 24 | -2.04 log10 copies/mL | Standard Error 0.244 |
| DRV/Rtv | Mean Change From Baseline to Week 24 and Week 48 in Plasma log10 Viral Load | Week 48 | -2.14 log10 copies/mL | Standard Error 0.257 |
Secondary
Number of Participants With Less Than or Equal to 1 log10 Decrease in Plasma Viral Load at Week 24 and Week 48
Time frame: Week 24 and Week 48
Population: 27 participants were recruited and received at least 1 dose of study medication; as Good Clinical Practice (GCP) requirements were not consistently adhered to at one site (involving 6 participant), analyses were performed excluding the participants from this site, resulting in 21 participants used for analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DRV/Rtv | Number of Participants With Less Than or Equal to 1 log10 Decrease in Plasma Viral Load at Week 24 and Week 48 | Week 24 | 17 Participants |
| DRV/Rtv | Number of Participants With Less Than or Equal to 1 log10 Decrease in Plasma Viral Load at Week 24 and Week 48 | Week 48 | 19 Participants |
Secondary
Number of Participants With Virological Response (Viral Load Less Than 400 Copies/mL) at Week 24 and Week 48
Time frame: Week 24 and Week 48
Population: 27 participants were recruited and received at least 1 dose of study medication; as Good Clinical Practice (GCP) requirements were not consistently adhered to at one site (involving 6 participant), analyses were performed excluding the participants from this site, resulting in 21 participants used for analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DRV/Rtv | Number of Participants With Virological Response (Viral Load Less Than 400 Copies/mL) at Week 24 and Week 48 | Week 24 | 17 Participants |
| DRV/Rtv | Number of Participants With Virological Response (Viral Load Less Than 400 Copies/mL) at Week 24 and Week 48 | Week 48 | 18 Participants |
Secondary
Number of Participants With Virological Response (Viral Load Less Than 50 Copies/mL) at Week 48
Time frame: Week 48
Population: 27 participants were recruited and received at least 1 dose of study medication; as Good Clinical Practice (GCP) requirements were not consistently adhered to at one site (involving 6 participant), analyses were performed excluding the participants from this site, resulting in 21 participants used for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DRV/Rtv | Number of Participants With Virological Response (Viral Load Less Than 50 Copies/mL) at Week 48 | 17 Participants |