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

This study has been terminated.
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by:
French National Agency for Research on AIDS and Viral Hepatitis
ClinicalTrials.gov Identifier:
NCT00122590
First received: July 20, 2005
Last updated: July 29, 2005
Last verified: July 2005
  Purpose

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.


Condition Intervention
HIV Infections
Drug: nelfinavir
Drug: lopinavir/r
Drug: indinavir
Drug: ritonavir

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Prospective Trial to Evaluate How Therapeutic Drug Monitoring of Protease Inhibitors Increases Virologic Success and Tolerance of HAART (ANRS 111 COPHAR2)

Resource links provided by NLM:


Further study details as provided by French National Agency for Research on AIDS and Viral Hepatitis:

Primary Outcome Measures:
  • 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

Secondary Outcome Measures:
  • 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

Estimated Enrollment: 115
Study Start Date: July 2002
Estimated Study Completion Date: March 2005
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00122590

Locations
France
Service de Medecine Interne Hopital Cochin
Paris, France, 75014
Sponsors and Collaborators
French National Agency for Research on AIDS and Viral Hepatitis
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
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00122590     History of Changes
Other Study ID Numbers: ANRS111 COPHAR 2
Study First Received: July 20, 2005
Last Updated: July 29, 2005
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by French National Agency for Research on AIDS and Viral Hepatitis:
protease inhibitors
nelfinavir
lopinavir
indinavir
Pharmacokinetics

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Protease Inhibitors
Indinavir
Ritonavir
Nelfinavir
Lopinavir
HIV Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 26, 2014