C L I N I C A L  T R I A L S  N E W S L E T T E R

INFORMATION FROM:
NATIONAL CENTRE IN HIV EPIDEMIOLOGY
AND CLINICAL RESEARCH
PHONE (02) 332 4648

DR. KATE CLEZY, kclezy@nchecr.unsw.edu.au
MR. JEFF HUDSON, jhudson@nchecr.unsw.edu.au




SEPTEMBER 1996 - LATEST NEWS - DELTA TRIALS

Expect Update Soon!

COMBINATION THERAPY IMPROVES SURVIVAL

The Data and Safety Monitoring Committee (DSMC) for Delta recentlymet and reviewed the data up to 31st May 1995. They concludedthat in Delta 1 participants (zidovudine naive) there is stronge vidence that combination therapy (AZT/ddI or AZT/ddC) yields substantial improvement in survival and reduction in the risk of progression to AIDS or death as compared to AZT monotherapy.However Delta 2 (for participants already exposed to AZT) did not indicate directly a clear benefit from combination therapy. The DSMC therefore recommended that both Delta 1 and 2 be discontinued which the Co-ordinating Committee endorsed.

SURVIVAL AND DISEASE PROGRESSION

Survival in Delta 1 was significantly better with combination therapy than monotherapy with an estimated reduction in mortality of 38%, however, the two combinations did not differ significantly:16.5% of 703 participants in the AZT group died compared with 9.6% of 720 in the AZT/ddI group and 11.6% of the 708 in the AZT/ddC group (global logrank p=0.0003). Similarly the AZT monotherapy group did significantly worse in terms of progression to AIDS or death than the combination groups (logrank p <0.0001): the proportions progressing to AIDS or death were 28.4% of 623, 17.6%of 630 and 23.3% of 615 respectively. Although there was a suggestion that the AZT/ddI group fared somewhat better in terms of progressionto AIDS or death than the AZT/ddC group (logrank p=0.03), the interpretation of this should await the results of subsequentanalyses with further data to 25th September, 1995.

In Delta 2 there were no significant differences between the groupsin terms of survival or disease progression; 26% of 355 participants in the AZT, 23% of 362 in the AZT/ddI and 26% of 366 in the AZT/ddC groups died and 39% of 297, 38% or 306 and 38% of 299, respectively,progressed to AIDS or died. Although data from Delta 2 did not show directly a clear benefit from combination therapy, they do not rule out a benefit from such combination.

The combined results from Delta 1 and Delta 2 yield a reduction in mortality of about 25% in favour of combination therapy (p=0.001).The initiation of antiretroviral chemotherapy with combinations of AZT plus ddl or AZT plus ddC conferred a substantial and highly significant benefit in terms of survival and progression to AIDS compared with AZT monotherapy.

The successful conclusion of this trial would not have been possible without the enthusiastic participation of investigators, research nurses, pharmacists, laboratory staff and most of all, the trial participants. We would like to thank all of you for the tremendous effort you put into this trial.

IL2 STUDY

Recruitment has continued with over 100 people now randomised in this study. This leaves only 5 or so more participants to complete enrolment. As independent panel of experts (a Data Safety Monitoring Board _DSMB) met in June to review progress in the trial. The DSMB recommended that the trial continue without any changes.

The trial has now demonstrated an appropriate dose of PEG-IL2.After repeated dose escalations, 11.5MU administered subcutaneouslyis well tolerated in an outpatient environment.

Some of the first people to recruit have now completed the 12 months of the original trial. These individuals are eligible to be considered for the continuation phase of the protocol. This stage provides a number of options for continuing access to IL2or PEG-IL2. If recruitment is completed in the near future then the final study results should be available toward the end of 1996.

AZT + 3TC STUDY

This study commenced enrolment in April 1995 and is recruiting patients in 24 sites. Approximately half of the patients enrolled are from hospital sites and half are from GP sites. The study compares three different treatments in patients with a CD4+ cellcount of between 25 - 250 cells/mL, who are generally zidovudine experienced. Eligible patients are randomised to one of the following treatment arms.

AZT (optional + ddI or ddC)

AZT + 3TC

AZT + 3TC + loviride

The study period is for one year and to date a total of 334 patient shave been enrolled in Australia. In June, Australia was allocated an additional 64 places which were divided among the initial centres.Internationally the study recruitment has been increased to 1600.This will give the study the power to detect smaller treatment differences between the three arms than originally intended and may allow a secondary analysis of patients who entered the studyon zidovudine monotherapy. The study medication appears well toleratedand to date there have been no serious adverse events reported.It is now critical that patients stay in the study for the 12months if they are tolerating the study drug in order to answer the research questions posed by the study.

What has become apparent over the last five months is that Australian trial sites have the ability to recruit and to perform well in a large phase III clinical trial.

PROSPECTIVE DATA COLLECTION

The role of prospective data collection in the analysis of diseases and their response to treatment is an essential part of clinicalresearch. Multiple case reports often lead to anecdotes which may not alway sbe helpful in gaining an understanding of the underlying disease.

This is especially true in uncommon conditions. Tuberculosis in HIV in Australia fortunately appears to be an uncommon condition about which there is limited information. A survey of patients with TB and HIV by Dr Peter Piggott reported in Noah's Ark, June1993 which retrospectively examined TB in 37 patients with HIV found that treatment was non-standard in 75% of patients and supervised in only 2 patients. He goes on to state:

Tuberculosis services were rarely used and contact procedures less than optimal, with resistance to the latter expressed by some medical carers, presumably because of confusion between confidentiality issues and responsibility of care.

Pulmonary TB was seen in 81% (30/37) and 70% were infectious (sputumpositive). In 16 of the 37, TB was the first significant illness and 23 had symptoms for more than four weeks prior to diagnosis with three patients having symptoms for six months prior to diagnosis.In this group of patients, almost half were born overseas and the median CD4+ cell count at presentation was 79mL (1 - 300).Tuberculosis occurring in HIV infected patients is usually reportedto occur early in the course of HIV infection. This is certainly true for countries with a high background prevalence of TB (egThailand).

As of December 1994, TB accounts for only 0.7% of AIDS diagnoses in Australia (there a total of 15 cases of TB as the AIDS defining condition on the database). The low numbers are partly reflected by the adoption in January 1993 of pulmonary TB as an AIDS defining condition. There were no notifications during 1993 of TB as an AIDS defining condition.

Despite the low numbers there is a very real risk of nosocomial transmission, as some of the predisposing conditions for the spreadof TB and the emergence of multidrug resistant (MDR) TB exist.In addition there is a lack of information about many aspects of TB in HIV patients. It is important to establish when and how TB is occurring in HIV infected patients, how tuberculosis is being treated in these patients, what are the clinical outcome,and what effect TB has on their survival and whether health careworkers are at risk for TB in the HIV setting.

To examine this further, the Opportunistic Infection Working Group of the National Centre in HIV Epidemiology and Clinical Researchhas developed a protocol for prospective data collection in patients who are co-infected with HIV and TB. The objectives of the protocol are to examine these questions as well as an attempt to assess the risks of nosocomial transmission of TB to health care workers,other patients and friends or family.

The data collection will be for two years from 1995. The protocol has been distributed to all major teaching hospitals in Australia for submission to Institutional Ethics Committees. If there are any other interested institutions who would like to participate in this data collection, please contact the secretary of the OIWG.

NATIONAL PRIORITY PROGRAM:
PEOPLE LIVING WITH HIV/AIDS AND THEIR CARERS

The PHACT Study (Participants in HIV/AIDS Clinical Trialsand Treatments) - The National Priority Program People Living with HIV/AIDS and their Carers' recently appointed a team of researchers, and hasbegun its mandate for social research. This priority program isone of three such programs under the National Centre in HIV Social Research.

From the consultation process established in 1994 to determine the affected communities' priorities for social research, three pathways for research were prioritised, each to form the basis for a number of projects.

The first pathway is that of Clinical Treatments and Trials. This research is being run in collaboration with the National Centrein HIV Epidemiology and Clinical Research (NCHECR) and Glaxo PtyLtd. The current drug trial for 3TC/Loviride has provided an initial setting for this study. Participants in the 3TC/Loviride trialare presently being invited to participate in the social arm ofthe study, and it is hoped to recruit as many participants as possible.

The PHACT study (Participants in HIV/AIDS Clinical Trials andTreatments) comprises two distinct phases. Phase I aims to investigate questions about participant satisfaction with a HIV clinical drug trial, decision-making influencing participants' behaviour whilst on a trial, and adherence to a trial regime. The researchers are presently in the process of recruiting patients who have enrolled in the 3TC/Loviride clinical trial through hospital sites around Australia. Participants will have a semi-structured questionnaires administered by an interviewer once a month for the duration of the trial.

In Phase II of the research, recruits will be drawn from those people who are presently receiving 3TC under the Special Access Scheme offered by Glaxo Australia, either through their general practitioner or hospital doctor. Those receiving the drug under the special Access Scheme will be asked to complete a self-administered questionnaire taking approximately 45 minutes, to be forwarded to participants by mail and returned by mail upon completion.The questionnaire asks a subset of the questions used in PhaseI.

This study has a number of benefits to participants of future HIV clinical drug trials and future recipients of promising HIV treatments. There are also benefits to current 3TC trial participants,including support from a person who understands clinical trials but is not part of the medical team. The results of this study will be used to improve the way in which future HIV clinical drug trials are run and will assist with future recruitment. This is to the benefit of both clinicians and people with HIV/AIDS.

The Program's Director is Dr Claire Parsons, an internationally-recognised sociologist with a background in Medical Sociology and Medical Anthropology and 5 years experience researching the social dimensions of HIV/AIDS. Dr Parsons leads an inter-disciplinary research team comprising 7 Melbourne-based and three Sydney-based researchers.Team members bring with them diverse experiences of working with HIV/AIDS from both community and professional standpoints, aswell as experiences of being gay and HIV positive. The program also supports post-graduate and casual researchers.

If you have any queries on the program or any of the research projects being undertaken, please fee free to contact Claire Parsonson (03) 9418 6909.

CURRENT CLINICAL TRIALS

INTERLEUKIN-2
Description: This is a phase II/III study comparing intravenous IL2 + antiretroviralsvs subcutaneous PEG-IL2 + antiretrovirals vs antiretroviral fortreatment of HIV infection.
Status: The study was opened in July 1994.
Sites: SVH, PHH, FID, RPA, WMH, RPH
Enrolled/target: 110 / 120
Sponsor: Chiron Therapeutics
Contact: Sean Emery
DELTA
Description: This study compares Zidovudine (ZDV) with ZDV + ddC vs ZDV + ddIin both ZDV experienced and ZDV naive patients.
Status: Delta closed to recruitment in June 1994.
Follow up:Will continue until December 1995.
Sites: All sites in the National Network
Enrolled/target: National: 321 / 330, International: 3305 / 3450
Sponsor: National Centre in HIV Epidemiology and Clinical Research
Contact: Contact Jeff Hudson and Kate Clezy
LIPOSOMAL AMPHOTERICIN
Description: This is an international multicentre study which compares the efficacy and safety of liposomal amphotericin (AmBisomer) vs amphotericinB (Fungizoner) for the initial treatment of cryptococcal meningitis in patients with AIDS.
Status: The study is continuing to recruit.
Sites: SVH, PHH, FID, RBH, WMH
Enrolled/target: National: 10 / 12, International: 24 / 32
Sponsor: Vestar Inc, David Bull
Contact: Kate Clezy
DELAVIRDINE
Description: This study looks at delavirdine (a non-nucleoside reverse transcriptaseinhibitor) + ZDV vs ZDV alone for the treatment of HIV infectionin HIV-positive patients with a CD4+ cell count of less than 350/mL.
Status: The multicentre study opened in August 1994.
Sites: SVH, PHH, WMH, FID, RAH, RBH, RMH
Enrolled/target: National: 12 /60 International: 236 / 1000
Sponsor: Upjohn
Contact: Jeff Hudson
SAQUINAVIR
Description: Saquinavir is a HIV-protease inhibitor which is entering multinationalphase III clinical trials. The study compares the following in HIV-positive patients who have had less than 16 weeks exposure to ZDV: ZDV alone vs ZDV + ddC vs ZDV + Saquinavir vs ZDV + ddC+ Saquinavir.
Status: The study was opened in September 1994.
Sites: SVH, PHH, FID, RBH, TSP, GCS, Cairns Hospital
Enrolled/target: National: 60 /120, International: 1059 /3000
Sponsor: Roche
Contact: Kate Clezy
INTERFERON-G AS AN ADJUNCTIVE THERAPY FOR MAC
Description: This study examines the efficacy and safety of adding s/c interferon-gto the combination of clarithromycin, rifabutin and ethambutol.
Status: Opened July 1994.
Sites: SVH, PHH, FID
Enrolled/target: 12 / 44
Sponsor: Boehringer Ingelheim
Contact: Kate Clezy
NEVIRAPINE (NVP) 1046
Description: A phase I I B combination study has opened at both National Centreand CHRN sites which compares AZT + ddI vs AZT + NVP vs AZT +NVP + ddI in anti-retroviral naive patients with CD4+ cell countof 200-600/mL.
Status: The study opened in August 1994.
Sites: SVH, PHH, RPH, FID, RBH, and CHRN sites
Enrolled/target: National: 23 / 40 International: 65 / 120
Sponsor: Boehringer Ingelheim
Contact: Kate Clezy
RADIOTHERAPY
Description: This is a study comparing two fractionated radiotherapy regimens for the palliation of Kaposi's sarcoma.
Status: Open to recruitment at SVH March 1995. Other sites willopen in April 1995.
Sites: SVH, TAH, PMC, HR
Enrolled/target: 140
Contact: Mark Newell
3TC™
Description: A randomised, double blind placebo controlled trial of AZT vsAZT/3TC™ vs AZT/3TC™/lovivide in HIV positive patients with CD4+ cell count 25 - 250/mm3.
Status: Open April 1995.
Sites: Sites 26 sites of NCHECR and CHRN
Enrolled/target: 334 / 330, International: 1600 / 1600
Sponsor: Glaxo
Contact: Kate Clezy
MERCK PROTEASE INHIBITOR (MK-639)
Description: A phase III, multi-clinic, double-blind, randomised, one yearstudy to compare the safety and efficacy of MK-639, 800mg Q8H administered concomitantly with stavudine, dosed by body weight,to that of MK-639 alone and stavudine alone.
Status: Open September 1995.
Sites: SVH, RBH
Enrolled/target: Enrolled/target 30 / 30
Sponsor: Merck Research Laboratories
Contact: Kate Clezy

NEUROLOGY TRIALS

DELAVIRDINE FOR AIDS DEMENTIA COMPLEX (ADC)
Description: This is a placebo-controlled study which compares the efficacy and safety of delavirdine with existing anti-retroviral therapy in mild to moderate ADC.
Status: Opened in October 1994.
Sites: SVH, FID
Enrolled/target: National: 6 / 18 , International: _ / 30
Sponsor: Upjohn
Contact: Bruce Brew
PEPTIDE T
Description: This is a dose response trial of Peptide T for AIDS Dementia.
Status: Due to open in early 1995, pending drug supply.
Sites: SVH, FID
Enrolled/target: National: _ / 18 , International: _ / 80
Sponsor: Peptech
Contact: Bruce Brew
AZT/DDI
Description: This is a study of the safety and efficacy of AZT and ddI forthe treatment of ADC
Status: Suspended
Sites: SVH, FID
Enrolled/target: 1/40
Sponsor: Bristol-Myers Squibb
Contact: Bruce Brew
ACTG 204
Description: This study compares low dose acyclovir vs high dose acyclovirvs valaciclovir for the prevention of cytomegalovirus end-organdisease in people with HIV infection with a CD4+ cell count of less than 100/mm3.
Status: Stopped in February 1995.
Sites: SVH, PHH, FID, RPH, TAH
Enrolled/target: National: 103 / 126, International: 1185 / 1200
Sponsor: Wellcome
Contact: Kate Clezy

CLOSED STUDIES

PROPHYLACTIC VACCINE STUDY
Description: This is a phase I study to look at the safety and immunogenicityof a prototype vaccine for HIV.
Status: The study has closed to recruitment.
Sites: SVH, HHG
Enrolled/target: 24 / 24
Sponsor: United Biomedical Inc, NY and University of New South Wales
Contact: Sean Emery
PHASE I STUDY OF G-CSF AND CEOP CHEMOTHERAPY OF THE TREATMENTOF NON-HODGKINS LYMPHOMA (NHL) IN PATIENTS WITH AIDS
Description: The primary aim of the study was to assess whether by adding G-CSF during chemotherapy for NHL, higher doses of chemotherapy could be given in combination with anti-retroviral therapy.
Status: Closed, manuscript in progress.
Sites: SVH, PHH, FID
Enrolled/target: 17/19
Sponsor: AMGEN
Contact: Mark Newell
DOXIL
Description: This study will examine the efficacy and safety of liposomal doxorubicinas a treatment of AIDS associated Kaposi's sarcoma.
Status: Withdrawn due to regulatory difficulties.
Sites: SVH, PHH, FID, others to be decided
Target: 50-60
Sponsor: LTI / UNSW
Contact: Mark Newell

PLANNED STUDIES

GANCICLOVIR FOR CMV RETINITIS
Description: An open randomised study of the safety and efficacy of intravenous ganciclovir (GCV) vs GCV implant vs GCV implant and oral GCV for the treatment of AIDS associated CMV retinitis.
Status: To open late 1995.
Sites: SVH, PHH, WMH, TAH, FIDH
Enrolled/target: _ / 18
Sponsor: Roche
Contact: Kate Clezy
1592
Description: This is a placebo-controlled study which compares the efficacy and safety of delavirdine with existing anti-retroviral therapy in mild to moderate ADC.
Status: To open early 1996.
Sites: SVH, FID
Enrolled/target: National: _ / 20
Sponsor: Glaxo / Wellcome
Contact: Bruce Brew

ABBREVIATIONS, ACRONYMS, AND OTHER JARGON

ASC - The Albion Street Clinic, Sydney
FMC - Flinders Medical Centre, Adelaide
FID - Fairfield Infectious Diseases Hospital, Melbourne
GCS - Gold Coast Sexual Health Clinic
HHG - Holdsworth House General Practice, Sydney
HR - Heidelberg Repatriation Hospital
IGP - Interchange General Practice, Canberra
PAH - Princess Alexandra Hospital, Brisbane
PHH - Prince Henry Hospital, Sydney
PKS - Port Kembla Sexual Health Clinic
PMC - Peter Mac Callum Cancer Institute
PSH - Parramatta Sexual Health Clinic
RAH - Royal Adelaide Hospital
RBH - Royal Brisbane Hospital
RDH - Royal Darwin Hospital
RHH - Royal Hobart Hospital
RMH - Royal Melbourne Hospital
RNS - Royal North Shore Hospital, Sydney
RPA - Royal Prince Alfred Hospital, Sydney
RPH - Royal Perth Hospital
SSH - Sydney Sexual Health Clinic
SVH - St Vincent's Hospital, Sydney
TAH - The Alfred Hospital, Melbourne
TSP - Taylor Square Private Clinic, Sydney
WMH - Westmead Hospital, Sydney
WVH - Woden Valley Hospital, Canberra

FURTHER INFORMATION

NATIONAL CENTRE IN HIV EPIDEMIOLOGY AND CLINICAL RESEARCH
PHONE (02) 332 4648

DR. KATE CLEZY, EMail: kclezy@nchecr.unsw.edu.au
MR. JEFF HUDSON, EMail: jhudson@nchecr.unsw.edu.au

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