A Study of Invirase (Saquinavir)/Ritonavir in HIV-Infected Infants and Children.

Study Overview
=================
Brief Summary
-----------------
This single arm study will assess the pharmacokinetics, safety and activity of saquinavir (Invirase hard gel capsules, film coated tablets or opened capsules) boosted by combination with ritonavir, in HIV-1 infected infants and children between the ages of 4 months and 6 years. Patients will commence treatment with saquinavir 50mg/kg bid plus ritonavir 2.5mg/kg or 3.0mg/kg (dependent on body weight), and a background antiretroviral regimen. If drug exposures are found to be dissimilar to those previously seen in older children and adults, or are associated with toxicities, subsequent dose adjustments will be made. The anticipated time on study treatment is 3-12 months, and the target sample size is <100 individuals.

Official Title
-----------------
A Phase I/II Study of Invirase® Boosted With Ritonavir in HIV Infected Infants and Children 4 Months to Less Than 6 Years Old

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Drug: ritonavir
* Drug: saquinavir [Invirase]


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: infants and children, 4 months to <6 years; confirmed HIV-1 infection; patients for whom saquinavir/ritonavir together with >=2 background ARVs is considered appropriate. Exclusion Criteria: body weight >4kg/8.8 pounds; use of any concomitant medications that may interfere with the pharmacokinetics of saquinavir or ritonavir; malabsorption, severe chronic diarrhea or vomiting within 28 days of the study.

Ages Eligible for Study
-----------------
Minimum Age: 4 Months
Maximum Age: 6 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: ritonavir<br>* 2.5-3.0mg/kg po bid (starting dose) for 48 weeks<br>Drug: saquinavir [Invirase]<br>* 50mg/kg po bid (starting dose) for 48 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Trough Concentrations (Ctrough) for Saquinavir | Plasma trough concentration is the average steady state concentration prior to morning and evening dose. Ctrough of Saquinavir was normalized to a dose of 50 mg/kg. | Pre-dose at Weeks 8, 12, 24. | 
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to Twelve Hours (AUC0-12h) for Saquinavir | The area under the plasma concentration-time curve from time zero to twelve hours (AUC0-12h) is area under the plasma concentration-time curve from time zero through actual tlast. The area under the plasma concentration-time curve from time zero to twelve hours of saquinavir was normalized to a dose of 50 mg/kg. | Pre-dose and 3, 4, 8, 12 hours (post-dose) on Day 14 (± 2 days), or Day 28(+ 2 days) for patients switching from an Non-nucleoside reverse transcriptase inhibitor [NNRTI] containing regimen). | 
| Incidence of Adverse Events (AE) and Serious Adverse Events (SAE) | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is a significant medical event in the investigator's judgment or requires intervention to prevent one or other of these outcomes | From Baseline (Day 1) till Week 48 and Follow-up (Week 52) | 
| Change In Hematocrit From Baseline | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1), Week 24 and Week 48 | 
| Change In Hemoglobin, Total Protein And Total Albumin From Baseline | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1), Week 24 and Week 48 | 
| Change In White Blood Cell (WBC), Platelet, Basophil, Lymphocyte, Monocyte, Neutrophil And Eosinophil Cell Counts From Baseline | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1), Week 24 and Week 48 | 
| Change In Red Blood Cell (RBC) Counts From Baseline | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1), Week 24 and Week 48 | 
| Change In Creatine Kinase (CK), Serum Glutamic Oxaloacetic Transaminase (SGOT), Alkaline Phosphatase (ALP), Serum Glutamic-Pyruvic Transaminase (SGPT), Gamma-Glutamyl Transferase (GGT) Counts From Baseline | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1), Week 24 and Week 48 | 
| Change In Total Bilirubin, Creatinine, Uric Acid From Baseline | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1), Week 24 and Week 48 | 
| Change In Blood Urea Nitrogen (BUN), Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL Cholesterol), Triglycerides, Calcium, Potassium, Sodium, Chloride, Phosphate, Fasting Glucose From Baseline | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1), Week 24 and Week 48 | 
| Change In Hematuria, Glycosuria And Proteinuria From Baseline | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1), Week 24 and Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With >1 Log Decrease From Baseline in Human Immunodeficiency Virus (HIV) -Ribonucleic Acid (RNA ) | The number of participants experiencing a greater than 1 log drop from baseline (day 1) (log 10 transformed) were reported | From Week 8 till Week 48 | 
| Number of Participants With Virological Failure | Virological failure was defined as: viral load >= 400 copies/mL on two consecutive occasions (missing visits was assumed to be above 400 copies/mL). The number of participants classified as virological failure by Age Group and viral load (≤ 10,000 copies, >10,000 copies) were presented. | From Week 12 till Week 48 | 
| Change From Baseline in Cluster Differentiation Antigen 4 (CD4) Lymphocyte Count | Change from Baseline in CD4+ lymphocyte count at 24 weeks and 48 weeks were presented by age group. Change from baseline in CD4+ lymphocyte count was derived as follows: Change from baseline = (CD4+ count at week 24/48) - (CD4+ count at baseline). A baseline collection was made if there was not already a value available taken within the previous 4 weeks. Baseline was on Day 1. | Baseline (Day 1), Weeks 8, 12, 24, 36, and 48 or upon premature discontinuation | 
| Change From Baseline in Cluster Differentiation Antigen 8 (CD8) Lymphocyte Count | Change from baseline in CD8+ lymphocyte count at 24 weeks and 48 weeks were presented by age group. Change from baseline in CD8+ lymphocyte count was derived as follows: Change from baseline = (CD8+ count at week 24/48) - (CD8+ count at baseline). A baseline collection was made if there was not already a value available taken within the previous 4 weeks. Baseline was on Day 1. | Baseline (Day 1), Weeks 8, 12, 24, 36, and 48 or upon premature discontinuation | 
| Plasma Trough Concentrations (Ctrough) for Ritonavir | Plasma trough concentration is the average steady state concentration prior to morning and evening dose. Ctrough of Ritonavir was normalized to a dose of 100 mg/kg. | Pre-dose at Weeks 8, 12, 24 | 
| Maximum Observed Concentration (Cmax) for Saquinavir and Ritonavir | The Plasma Concentration (Cmax) is defined as maximum observed analyte concentration. Cmax was normalized to a dose of 50 mg/kg for Saquinavir and100 mg/kg for Ritonavir. | Pre-dose and 3, 4, 8, 12 hours (post-dose) on Day 14 (± 2 days), or Day 28(+ 2 days) for patients switching from an NNRTI containing regimen and at Week 24 | 
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to Twelve Hours (AUC0-12h) for Ritonavir | The area under the plasma concentration-time curve from time zero to twelve hours (AUC0-12h) is area under the plasma concentration-time curve from time zero through actual tlast. The area under the plasma concentration-time curve from time zero to twelve hours of ritonasvir was normalized to a dose of 100 mg/kg. | Pre-dose and 3, 4, 8, 12 hours (post-dose) on Day 14 (± 2 days), or Day 28(+ 2 days) for patients switching from an NNRTI containing regimen). | 
| Change From Baseline in Mean Human Immunodeficiency Virus Viral Load | Change from baseline in plasma HIV-1 RNA was derived as Change from baseline = Log10 (HIV-1 RNA at week x) - Log10 (HIV-1 RNA at baseline) | Baseline (Day 1), Weeks 8, 12, 24, 36, and 48 (or upon premature discontinuation); a baseline collection was made if there was not already a value available taken within the previous 4 weeks. | 
| Number of Participants With Human Immunodeficiency Virus (HIV) -Ribonucleic Acid (RNA) <400 Copies/mL | The number of participants with HIV-1 RNA results <400 copies/mL were reported | Baseline (Day 1), Weeks 8, 12, 24, 36, and 48 (or upon premature discontinuation); a baseline collection was made if there was not already a value available taken within the previous 4 weeks. | 
| Number of Participants With Human Immunodeficiency Virus (HIV) -Ribonucleic Acid (RNA) <50 Copies/mL | The number of participants with HIV-1 RNA results <50 copies/mL were reported. | Baseline (Day 1), Weeks 8, 12, 24, 36, and 48 (or upon premature discontinuation); a baseline collection was made if there was not already a value available taken within the previous 4 weeks. |