Evaluation of Therapeutic Drug Monitoring of Protease Inhibitors on Virologic Success and Tolerance of Highly Active Antiretroviral Therapy (HAART)

Tracking Information
First Submitted Date ICMJE	July 20, 2005
First Posted Date ICMJE	July 22, 2005
Last Update Posted Date	August 1, 2005
Study Start Date ICMJE	July 2002
Primary Completion Date	Not Provided
Current Primary Outcome Measures ICMJE; (submitted: July 28, 2005)	treatment failure defined as viral load greater than 200 copies/ml between week 16 (W16) and week 48 (W48) (confirmed by 2 samples spiked at least 15 days apart but no more than 45 days after virological failure, assayed by 50 copies/ml method); toxicity related to PI, defined as adverse event grade 3 or 4 with ANRS quotation, renal colic, diarrhoea grade 2, or cholesterolemia over 10 times the normal value
Original Primary Outcome Measures ICMJE; (submitted: July 20, 2005)	treatment failure defined as viral load over 200 copies between W16 and W48 (confirmed by 2 samples spiked at least 15 days apart but no more than 45 days after virological failure, assayed by 50 copies/ml method); or toxicity related to PI, defined as adverse event grade 3 or 4 with ANRS quotation, or renal colic, or diarrhoea grade 2, or cholesterolemia over 10 times the normal value
Change History	Complete list of historical versions of study NCT00122590 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: July 28, 2005)	virological failure: viral load over 200 copies/ml between W16 and W48 (confirmed by 2 samples spiked at least 15 days apart but no more than 45 days after virological failure, assayed by 50 copies/ml method); toxicity related to PI: adverse events grade 3 or 4 with ANRS quotation, renal colic, diarrhoea grade 2, or cholesterolemia over 10 times the normal value; patients with trough plasma concentrations outside the therapeutic range at W24 and W48; concentration changes with dosage variation; time to obtain a viral load below 200 copies/ml; relationship between adverse events grade 3 or 4 related to PI and plasma concentration at week 2 (W2); relationship between pharmacokinetic parameters and/or plasma concentrations and the drop of viral load between day 0 (D0) and W2 and between D0 and week 4 (W4); relationship between pharmacokinetic parameters and viral mutations occurring during the treatment of patients with virological failure (over 1000 copies/ml after week 24 [W24]); PI pharmacokinetic parameter estimation and evaluation of variability; pharmacokinetic variability of nucleoside analogues at W2; intracellular concentration of nucleoside triphosphate derivatives at W2 (trough and maximum) and relationship between virological response and adverse events; relationship between inhibitory quotient of indinavir and virological response
Original Secondary Outcome Measures ICMJE; (submitted: July 20, 2005)	virological failure : viral load over 200 copies between W16 and W48 (confirmed by 2 samples spiked at least 15 days apart but no more than 45 days after virological failure, assayed by 50 copies/ml method); Toxicity related to PI : adverse events grade 3 or 4 with ANRS quotation, or renal colic, or diarrhoea grade 2, or cholesterolemia over 10 times the normal value; patients with trough plasma concentrations outside the therapeutic range at W24 and W48; concentration changes with dosage variation; time to obtain a viral load below 200 copies/ml; Relationship between adverse events grade 3 or 4 related to PI and plasma concentration at W2; Relationship between pharmacokinetic parameters and/or plasma concentrations and the drop of viral load between D0 and W2 and between D0 and W4; Relationship between pharmacokinetic parameters and viral mutations occurring during the treatment of patients with virological failure (over 1000 copies/ml after W24); PI pharmacokinetic parameter estimation and evaluation of variability; pharmacokinetic variability of nucleoside analogues at W2; intracellular concentration of nucleoside triphosphate derivatives at W2 (trough and maximum) and relationship between virological response and adverse events; relationship between inhibitory quotient of indinavir and virological response
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Evaluation of Therapeutic Drug Monitoring of Protease Inhibitors on Virologic Success and Tolerance of Highly Active Antiretroviral Therapy (HAART)
Official Title ICMJE	Prospective Trial to Evaluate How Therapeutic Drug Monitoring of Protease Inhibitors Increases Virologic Success and Tolerance of HAART (ANRS 111 COPHAR2)
Brief Summary	This Cophar2 study is a trial which evaluates repeated early therapeutic drug monitoring, from weeks 2 to 24, after the initiation of HAART including either indinavir/r, lopinavir/r or the new 625 mg formulation of nelfinavir twice-a-day (bid). If trough concentrations were out of the range given for each protease inhibitor (PI), the PI dose was adjusted.
Detailed Description	Because of the large pharmacokinetic inter-patient variability of protease inhibitors (PI), therapeutic drug monitoring (TDM) of protease inhibitor (PI) has been proposed to improve efficacy and tolerance of PI-containing HAART. The objective of the Cophar2 trial is to evaluate the feasibility and the impact of an early therapeutic drug monitoring in PI-naive HIV-1 infected patients in order to warrant virological success and safety of HAART. It is a prospective, open, multicenter trial with repeated early TDM (weeks 2, 8 or 16, 24) after the initiation of HAART including either indinavir/r (IDV), lopinavir/r (LPV) or the new 625 mg formulation of nelfinavir (NFV) bid. It was planned to include 99 PI-naïve HIV-1 infected patients over 18 years old, 33 for each PI. Concentrations were measured by HPLC in each center. If trough concentrations were out of the range of 150-500, 2500-7000 or 1500-5500 ng/ml for IDV, LPV and NFV respectively, the PI doses were adjusted possibly more than once during the first 24 weeks of follow-up. Adjustments were done by steps of one pill (200, 133/33 or 250 mg for IDV, LPV/r or NFV, respectively) bid. Failure of the strategy was defined by either two consecutive viral loads over 200 copies/ml between weeks 16 and 48, or a validated PI-related adverse event grade III or IV or a grade II diarrhoea or renal lithiasis. Patients without adverse events before week 16 were defined as assessable if they had at least the virological assessment of week 16.
Study Type ICMJE	Interventional
Study Phase	Not Applicable
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	HIV Infections
Intervention ICMJE	Drug: nelfinavir; Drug: lopinavir/r; Drug: indinavir; Drug: ritonavir
Study Arms	Not Provided
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Terminated
Enrollment ICMJE; (submitted: July 20, 2005)	115
Original Enrollment ICMJE	Same as current
Study Completion Date	March 2005
Primary Completion Date	Not Provided
Eligibility Criteria ICMJE	Inclusion Criteria: Patients infected with HIV-1; Needing an antiretroviral treatment according to standard of care; HIV viral load greater than 1000 copies/ml; Beginning a treatment containing a PI (indinavir with or without ritonavir, nelfinavir, lopinavir + ritonavir) and 2 reverse transcriptase inhibitors; PI-naive; Antiretroviral treatment-naive or already treated with reverse transcriptase inhibitors but if the viral genotypic test does not show more than 2 major mutations (including T215Y/F, Q151M, M184V/I, V75M/S, L74V) and if 3 nucleoside analogues are still active except for didanosine. Exclusion Criteria: Pregnant women and nursing mothers; Acute HIV infection; Diabetes; Renal insufficiency with creatinine clearance below 30 ml/min; Cardiac insufficiency; Hepatic insufficiency with TP below 60%; Treatment with known interactions with PI; Chemotherapy against Kaposi's sarcoma, lymphoma, neoplasia; Treatment containing interferon (INF) or interleukin-2 (IL2) or HIV- immune vaccine; Treatment with hypolipemic drugs; Laxative treatment; Previous renal colic; Diarrhoea with more than 5 stools/day since one week
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	France
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00122590
Other Study ID Numbers ICMJE	ANRS111 COPHAR 2
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Not Provided
Study Sponsor ICMJE	French National Agency for Research on AIDS and Viral Hepatitis
Collaborators ICMJE	Hoffmann-La Roche
Investigators ICMJE	Principal Investigator: Dominique Salmon, MD Service de Medecine Interne Hopital Cochin Paris Study Chair: France Mentre, MD Inserm EMI 03 57
PRS Account	French National Agency for Research on AIDS and Viral Hepatitis
Verification Date	July 2005
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP