A Phase I Multiple Dose Pharmacokinetic Study of Nevirapine Extended Release (XR) in HIV-1 Infected Children.

Study Overview
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Brief Summary
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The primary objective is to establish the pharmacokinetic (PK) profile at steady state of nevirapine XR in HIV infected children from >=3 to <18 years of age. This phase I trial is an open-label, multiple dose, non-randomized and cross-over study. Patients who have completed the last visit of the PK trial (visit 7) can enter into an Optional Extension Phase (OEP) until the Investigational New Drug (IND) is withdrawn; until nevirapine XR becomes approved and is available by prescription in a given country; or, the patient enrolls in a compassionate use program. During this OEP, nevirapine XR safety and efficacy information will be collected.

Official Title
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An Open-label, Multiple Dose, Cross-over Study to Evaluate the Steady-state Pharmacokinetic Parameters of Nevirapine Extended Release Tablets in HIV-1 Infected Children, With an Optional Extension Phase

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Nevirapine Immediate Release (IR)
* Drug: Nevirapine Extended Release (XR)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed and dated written informed consent of a parent or legal guardian prior to admission. Active assent must be given by the patient if the child and/or adolescent is capable of understanding the provided study information. HIV-1 infected males or females >= 3 and < 18 years old. BSA >= 0.58 m2 for patients using BSA to calculate nevirapine IR dose; or BW >= 12.5 kg for patients using BW to calculate nevirapine IR dose at screening visit. Treated with a nevirapine IR based regimen for at least 18 weeks prior to screening visit (Visit 1); no modifications in the ARV background therapy within the last 2 weeks prior to screening. An HIV VL of <50 copies/mL while receiving nevirapine IR at the last measure of VL documented in the medical record obtained within a period of 5 months prior to screening visit. An HIV VL of <50 copies/mL at screening visit. A stable or not decreasing CD4+ cell count according to the investigator's opinion. Acceptable screening laboratory values that indicate adequate baseline organ function according to the opinion of investigator. ALT and AST <= 2.5 X ULN (DAIDS Grade 1). Serum creatinine levels <= 1.3 X ULN (DAIDS Grade 1). Patients able to swallow tablets. Exclusion criteria: Any AIDS-related or AIDS defining illness that is unresolved or not stable on treatment at least 8 weeks prior to screening visit. Diseases other than HIV infection or conditions that, in the investigator's opinion, would interfere with the study. Patients who have been diagnosed with malignant disease and who are receiving systemic chemotherapy or are anticipated to receive any therapy during their participation in this trial. Use of investigational medications or vaccines within 28 days prior to Visit 1 or during the trial. Use of immunomodulatory drugs within 28 days before Visit 1 or during the trial (e.g., interferon, cyclosporin, hydroxyurea, interleukin 2). Concomitant protease inhibitor (PI) treatment. Unwillingness to abstain from ingesting substances during the study which may alter plasma drug concentrations by interaction with the cytochrome P450 system (Appendix 10.2). Female patients of childbearing potential who: have a positive serum pregnancy test at screening, are breast feeding, are planning on becoming pregnant, are not willing to use double-barrier methods

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nevirapine IR / Nevirapine XR<br>In this pharmaco-kinetic (PK) cross-over design trial, all patients initially receive nevirapine immediate release and then all patients are switched to nevirapine extended release 200 mg, 300 mg or 400 mg QD. After completing the PK phase patients had the option of continuing treatment with nevirapine XR in the Optional Extension Phase (OEP). | Drug: Nevirapine Immediate Release (IR)<br>* 200 mg Tablet or 50 mg / 5 ml oral suspension<br>* Other names: Nevirapine IR;Drug: Nevirapine Extended Release (XR)<br>* 200 mg, 300 mg or 400 mg Tablet formulation<br>* Other names: Nevirapine XR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Cpre,N. | Trough Nevirapine concentration immediately prior to the next scheduled dose. Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22. The measure of dispersion presented is the coefficient of variation (%) rather than the geometric coefficient of variation. | Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCt,ss | Area under the concentration-time curve of the Nevirapine (NVP) in plasma at steady state over the time dosing interval τ. All patients received nevirapine IR for 10 days prior to collection of 12-hour Area Under the Curve (AUC) data. Then, all patients were switched to nevirapine XR for 9 days prior to collection of 24-hour AUC data. The treatments of IR and XR are summarized separately using geometric means and geometric coefficients of variation. For NVP IR AUC measured over hours: 0,1,2,3,4,8 and 12, For NVP XR AUC measured over hours: 0,1,2,3,4,8,10,12 and 24. | Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR | 
| Cmin,ss (for IR and XR Formulations by Nevirapine XR Dose Group) | Minimum measured concentration of the Nevirapine in plasma at steady state over the time dosing interval τ by nevirapine XR dose group Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 21. | Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR | 
| Cmax,ss (for IR and XR Formulations by Nevirapine XR Dose Group) | Maximum measured concentration of the Nevirapine in plasma at steady state over the time dosing interval τ Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22. | Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR | 
| Ratio Cmax,ss/Cmin,ss | Ratio of (maximum measured concentration of the Nevirapine in plasma at steady state over the time dosing interval τ)/(minimum measured concentration of the analyte in plasma at steady state over the time dosing interval τ) Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22. | Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR | 
| %PTF | Percentage peak-trough Nevirapine fluctuation, % fluctuation (degree of peak to trough fluctuation) Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22. | Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR | 
| Tmax,ss | Time from dosing to the maximum concentration of the Nevirapine in plasma at steady state over the time dosing interval τ Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22. The standard deviation is actually the coefficient of variation. | Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR | 
| CL/F,ss | Apparent clearance of the Nevirapine in the plasma after extravascular administration at steady-state Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22. | Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR | 
| Cavg | Average measured concentration of the Nevirapine in plasma at steady state Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22. | Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR | 
| Efficacy: Patients Maintaining a VL < 50 Copies/mL | Patients maintaining a viral load < 50 copies/mL at Day 22. | Day 22 | 
| Efficacy: Patients Maintaining a VL < 400 Copies/mL | Patients maintaining a viral load < 400 copies/mL at Day 22 | Day 22 | 
| Change From Baseline in Mean CD4+ Count (Absolute) | Change in mean CD4+ count (absolute) from baseline to Day 22 and from baseline to Week 24. | Baseline, Day 22 and week 24 | 
| Percentage Change From Baseline in Mean CD4+ Count | ((Day 22 value-Baseline value)/Baseline value)*100. ((Week 24 value-Baseline value)/Baseline value)*100. | Baseline to day 22 and baseline to week 24 | 
| Efficacy: Patients Maintaining a VL < 50 Copies/mL at Week 24 of Optional Extension Phase | Patients maintaining a viral load < 50 copies/mL at week 24 (approximately 168 days) of Optional Extension Phase (OEP). | week 24 | 
| Efficacy: Patients Maintaining a VL < 400 Copies/mL in Optional Extension Phase | Patients maintaining a viral load < 400 copies/mL at week 24 of the Optional Extension Phase (OEP) | week 24 |