Phase I/II dose escalation and randomized withdrawal study with add-on azodicarbonamide in patients failing on current antiretroviral therapy

Goebel, Frank-D.a; Hemmer, Robertb; Schmit, Jean-Claudeb; Bogner, Johannes R.a; Clercq, Erik dec; Witvrouw, Myriamc; Pannecouque, Christophec; Valeyev, Rustemd; Vandevelde, Michele; Margery, Hélènee; Tassignon, Jean-Pierref

Clinical Science

Background: Azodicarbonamide (ADA), a HIV-1 zinc finger inhibitor, targets a new step in viral replication and cell infectivity.

Objective: A first phase I/II clinical study of ADA.

Methods: ADA was administered at escalating doses concomitantly with current antiviral therapy during a 3-month open-label period in patients with advanced AIDS and documented virological failure. After 3 months, patients were randomized in a double-blind placebo-controlled withdrawal, ADA being given at the highest tolerated dosage.

Results: Fifteen patients with advanced disease failing on combined antiretroviral therapy, 75% of them with proven phenotypic resistance, had a median baseline CD4 cell count of 85 × 106 cells/l, CD4/CD8 cell ratio of 0.09 and median plasma RNA viral load of 4.2 log10 copies/ml. Tolerance to ADA was dose dependent and some patients developed nephrolithiasis, glucose intolerance or showed an ADA-related cytotoxicity towards CD4 cells at higher dosages. No patient died during the study period. ADA increased CD4 cell percentage, increased the CD4/CD8 cell ratio and decreased plasma RNA viral load from baseline. At the end of the double-blind period, the ADA group, but not the placebo group, showed a significant response (P < 0.05). No phenotypic resistance to ADA was observed. Overall, 3/11 patients (27%) had consistent viral load reductions > 0.5 log10 copies/ml compared with baseline and 5/11 (45%) showed a CD4 cell recovery from baseline > 33%. In responders, ADA induced a median peak increase in CD4 cell percentage change from baseline of 65% (range 47–243%), and viral load decrease of 1.04 log10 copies/ml (range 0.52–1.23).

Conclusions: The maximal tolerated dosage of ADA appears to be 2 g (three times daily). This study provides safety results that will allow larger clinical trials to confirm the preliminary efficacy data.

Author Information

From the aMedizinische Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany, the bInfectious Diseases Department, Centre, Hospitalier de Luxembourg, Luxembourg, the cAIDS Laboratory, Rega Institute of Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium, the dData Management Department, PSI Pharma Support A.G., Zug, Switzerland, the eR&D Department, Hubriphar S.A., Brussels, Belgium and fClinical Operations Department, Tassignon & Partners S.A., Brussels, Belgium.

Received: 27 March 2000;

revised: 28 June 2000; accepted: 7 July 2000.

Requests for reprints to: Dr F.-D. Goebel, Med. Poliklinik, Pettenkoferstr. 8a,80336 München, Germany.

Sponsorship: This research was supported by a grant from Hubriphar S.A. The virology research and the development of an analytical method in blood and urine were supported by grants from the Government of the Region of Brussels.

© 2001 Lippincott Williams & Wilkins, Inc.