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

• ClinicalTrials.gov Identifier: NCT00122590
• Recruitment Status: Terminated
• First Posted: July 22, 2005
• Last Update Posted: August 1, 2005
• Sponsor: French National Agency for Research on AIDS and Viral Hepatitis
• Collaborator: Hoffmann-La Roche
• Information provided by: French National Agency for Research on AIDS and Viral Hepatitis

Tracking Information

• First Submitted Date: July 20, 2005
• First Posted Date: July 22, 2005
• Last Update Posted Date: August 1, 2005
• Study Start Date: July 2002
• Primary Completion Date: Not Provided

Current Primary Outcome Measures (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 (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

Current Secondary Outcome Measures (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 (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 Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Therapeutic Drug Monitoring of Protease Inhibitors on Virologic Success and Tolerance of Highly Active Antiretroviral Therapy (HAART)
• Official Title: 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: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV Infections

Intervention

• Drug: nelfinavir
• Drug: lopinavir/r
• Drug: indinavir
• Drug: ritonavir

• Study Arms: Not Provided
• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Enrollment (submitted: July 20, 2005): 115
• Original Enrollment: Same as current
• Study Completion Date: March 2005
• Primary Completion Date: Not Provided

Eligibility Criteria

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: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT00122590
• Other Study ID Numbers: 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: French National Agency for Research on AIDS and Viral Hepatitis
• Collaborators: Hoffmann-La Roche

Investigators

• 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