A Phase I Multiple Dose Pharmacokinetic Study of Nevirapi... | NCT00905489

ID	Type	Description	Link
2008-005855-61	EudraCT Number	EudraCT

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Nevirapine IR / Nevirapine XR	Experimental	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) Drug: Nevirapine Extended Release (XR)

Name	Type	Description	Arm Group Labels	Other Names
Nevirapine Immediate Release (IR)	Drug	200 mg Tablet or 50 mg / 5 ml oral suspension	Nevirapine IR / Nevirapine XR

Outcomes Module

Primary Outcomes

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 Outcomes

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.

Other Outcomes

Measure	Description	Time Frame
Efficacy: Patients Maintaining a VL < 50 Copies/mL at Last Available Visit	Patients maintaining a viral load < 50 copies/mL at the last available visit	Last available visit, up to 155 weeks

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
1100.1518.0001 Boehringer Ingelheim Investigational Site		Washington D.C.	District of Columbia		United States

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Total.	All patients enrolled in study. All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 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).

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

ID	Title	Description
BG000	Total.	All patients enrolled in study. All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 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).

Units	Counts
Participants	BG00085

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

PK analysis set (PKS): This patient set includes all patients in the Full Analysis Set (FAS) set that have no protocol violations excluding them from PK analyses.

Posted

Geometric Mean

Geometric Coefficient of Variation

(ng/mL/mg)

Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR

ID	Title	Description
OG000	NVP XR	Nevirapine XR (extended release)
OG001	NVP IR	Nevirapine IR (immediate release)

Units	Counts
Participants	OG00074 OG00178

Title

Denominators

Categories

Title	Measurements
	OG00015.47± 64.34 OG00116.66± 75.03

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Mixed Models Analysis	Adjusted geometric means are estimated from the mixed model for intra-individual comparison.	0.0080		Ratio NVP XR: NVP IR (%)	91.20	Standard Error of the Mean	1.05	2-Sided	90	83.47	99.64				No	Superiority or Other

Secondary

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.

Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*h/ml

Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR

ID	Title	Description
OG000	NVP XR	Nevirapine XR (extended release)
OG001	NVP IR	Nevirapine IR (immediate release)

Units	Counts
Participants

Secondary

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.

Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR

ID	Title	Description
OG000	NVP XR	Nevirapine XR (extended release)
OG001	NVP IR	Nevirapine IR (immediate release)

Units	Counts
Participants	OG000

Secondary

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.

Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR

ID	Title	Description
OG000	NVP XR	Nevirapine XR (extended release)
OG001	NVP IR	Nevirapine IR (immediate release)

Units	Counts
Participants	OG000

Secondary

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.

Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.

Posted

Geometric Mean

Geometric Coefficient of Variation

Ratio

Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR

ID	Title	Description
OG000	NVP XR	Nevirapine XR (extended release)
OG001	NVP IR	Nevirapine IR (immediate release)

Units	Counts
Participants

Secondary

%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.

Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.

Posted

Geometric Mean

Geometric Coefficient of Variation

percentage fluctuation

Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR

ID	Title	Description
OG000	NVP XR	Nevirapine XR (extended release)
OG001	NVP IR	Nevirapine IR (immediate release)

Units	Counts
Participants	OG000

Secondary

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.

Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.

Posted

Mean

Standard Deviation

hours

Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR

ID	Title	Description
OG000	NVP XR	Nevirapine XR (extended release)
OG001	NVP IR	Nevirapine IR (immediate release)

Units	Counts
Participants	OG000

Secondary

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.

Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.

Posted

Geometric Mean

Geometric Coefficient of Variation

mL/h

Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR

ID	Title	Description
OG000	NVP XR	Nevirapine XR (extended release)
OG001	NVP IR	Nevirapine IR (immediate release)

Units	Counts
Participants	OG000

Secondary

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.

Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR

ID	Title	Description
OG000	NVP XR	Nevirapine XR (extended release)
OG001	NVP IR	Nevirapine IR (immediate release)

Units	Counts
Participants	OG000

Secondary

Efficacy: Patients Maintaining a VL < 50 Copies/mL

Patients maintaining a viral load < 50 copies/mL at Day 22.

Full analysis set including patients with available viral load data at day 22

Posted

Number

percentage of patients

Day 22

ID	Title	Description
OG000	3-<6 yr	Patients 3 to < 6 years old.
OG001	6-<12 yr	Patients 6 to < 12 years old.
OG002	12-<18 yr	Patients 12 to < 18 years old.
OG003	Total.	All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 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).

Secondary

Efficacy: Patients Maintaining a VL < 400 Copies/mL

Patients maintaining a viral load < 400 copies/mL at Day 22

Full analysis set including patients with available viral load data at day 22

Posted

Number

percentage of patients

Day 22

ID	Title	Description
OG000	3-<6 yr	Patients 3 to < 6 years old.
OG001	6-<12 yr	Patients 6 to < 12 years old.
OG002	12-<18 yr	Patients 12 to < 18 years old.
OG003	Total.	All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 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).

Secondary

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.

PK Analysis set: This patient set includes all patients in the Full Analysis Set (FAS) that have no protocol violations excluding them from PK analysis.

Posted

Mean

Standard Deviation

cells/mm^3

Baseline, Day 22 and week 24

ID	Title	Description
OG000	3-<6 yr	Patients 3 to < 6 years old.
OG001	6-<12 yr	Patients 6 to < 12 years old.
OG002	12-<18 yr	Patients 12 to < 18 years old.

Units	Counts
Participants	OG000

Secondary

Percentage Change From Baseline in Mean CD4+ Count

((Day 22 value-Baseline value)/Baseline value)*100. ((Week 24 value-Baseline value)/Baseline value)*100.

Optional Extension Phase Treated Set (OEP TS), all patients that complete PK phase and enroll in Extension phase, and had available data at either day 22 or week 24.

Posted

Mean

Standard Deviation

percentage change

Baseline to day 22 and baseline to week 24

ID	Title	Description
OG000	3-<6 yr	Patients 3 to < 6 years old.
OG001	6-<12 yr	Patients 6 to < 12 years old.
OG002	12-<18 yr	Patients 12 to < 18 years old.

Units	Counts
Participants	OG000

Secondary

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).

Full analysis set including patients with available viral load data at week 24

Posted

Number

percentage of patients

week 24

ID	Title	Description
OG000	3-<6 yr	Patients 3 to < 6 years old.
OG001	6-<12 yr	Patients 6 to < 12 years old.
OG002	12-<18 yr	Patients 12 to < 18 years old.
OG003	Total.	All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 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).

Secondary

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)

Full analysis set including patients with available viral load data at week 24

Posted

Number

percentage of patients

week 24

ID	Title	Description
OG000	3-<6 yr	Patients 3 to < 6 years old.
OG001	6-<12 yr	Patients 6 to < 12 years old.
OG002	12-<18 yr	Patients 12 to < 18 years old.
OG003	Total.	All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 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).

Other Pre-specified

Efficacy: Patients Maintaining a VL < 50 Copies/mL at Last Available Visit

Patients maintaining a viral load < 50 copies/mL at the last available visit

Optional Extension Phase Treated Set (OEP TS), all patients that complete PK phase and enroll in Extension phase with VL data available

Posted

Number

percentage of patients

Last available visit, up to 155 weeks

ID	Title	Description
OG000	3-<6 yr	Patients 3 to < 6 years old.
OG001	6-<12 yr	Patients 6 to < 12 years old.
OG002	12-<18 yr	Patients 12 to < 18 years old.
OG003	Total.	All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 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).

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Total.	All patients enrolled in study. All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 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).			3	85	56	85

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Coxsackie viral infection	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG0001 affected85 at risk
Pneumonia	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG0001 affected85 at risk
Concussion	Injury, poisoning and procedural complications	MEDDRA 15.0	Systematic Assessment	EG0001 affected85 at risk
Fall	Injury, poisoning and procedural complications	MEDDRA 15.0	Systematic Assessment	EG0001 affected85 at risk
Dermatitis	Skin and subcutaneous tissue disorders	MEDDRA 15.0	Systematic Assessment	EG0001 affected85 at risk
Tonsillectomy	Surgical and medical procedures	MEDDRA 15.0	Systematic Assessment	EG0001 affected85 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Conjunctivitis	Eye disorders	MEDDRA 15.0	Systematic Assessment	EG00011 affected85 at risk
Diarrhoea	Gastrointestinal disorders	MEDDRA 15.0	Systematic Assessment	EG0005 affected85 at risk
Vomiting	Gastrointestinal disorders	MEDDRA 15.0	Systematic Assessment	EG0007 affected85 at risk
Pyrexia	General disorders	MEDDRA 15.0	Systematic Assessment	EG0008 affected85 at risk
Body tinea	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG0005 affected85 at risk
Bronchitis	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG0005 affected85 at risk
Nasopharyngitis	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG0005 affected85 at risk
Respiratory tract infection	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG0006 affected85 at risk
Rhinitis	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG0008 affected85 at risk
Tinea capitis	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG0007 affected85 at risk
Upper respiratory tract infection	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG00033 affected85 at risk
Viral upper respiratory tract infection	Infections and infestations	MEDDRA 15.0	Systematic Assessment	EG0009 affected85 at risk
Headache	Nervous system disorders	MEDDRA 15.0	Systematic Assessment	EG00014 affected85 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MEDDRA 15.0	Systematic Assessment	EG00028 affected85 at risk
Rash	Skin and subcutaneous tissue disorders	MEDDRA 15.0	Systematic Assessment	EG00020 affected85 at risk

ID	Term
D000086982	Blood-Borne Infections
D003141	Communicable Diseases
D007239	Infections
D015229	Sexually Transmitted Diseases, Viral
D012749	Sexually Transmitted Diseases
D016180	Lentivirus Infections
D012192	Retroviridae Infections
D012327	RNA Virus Infections
D014777	Virus Diseases
D000091662	Genital Diseases
D000091642	Urogenital Diseases
D007153	Immunologic Deficiency Syndromes
D007154	Immune System Diseases

ID	Term
D011725	Pyridines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds