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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: ritonavir; Drug: saquinavir [Invirase]

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1425
  • Buenos Aires, Argentina, 1202
  • Santa Fe, Argentina, 3000
• Spain
  • Madrid, Spain, 28046
  • Madrid, Spain, 28905
  • Valencia, Spain, 46009
• Thailand
  • Bangkok, Thailand, 10400
  • Khon Kaen, Thailand, 40002
  • Pathumwan, Thailand, 10330
  • Payathai, Thailand, 10400

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 6 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

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

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
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.
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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: February 18, 2008
• First Submitted That Met QC Criteria: February 18, 2008
• First Posted (Estimate): February 26, 2008

Study Record Updates

• Last Update Posted (Estimate): March 7, 2016
• Last Update Submitted That Met QC Criteria: February 4, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Saquinavir
• Other Study ID Numbers: NV20911; 2007-004617-34

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES