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An Efficacy Study of 2',3'-Dideoxyinosine (ddI) (BMY-40900) Administered Orally Twice Daily to Zidovudine Intolerant Patients With AIDS or AIDS-Related Complex

11 de março de 2011 atualizado por: National Institute of Allergy and Infectious Diseases (NIAID)

AMENDED: 8/29/90 Inclusion of asymptomatic patients with CD4 counts less than 200 cells/mm3. Standardization of baseline evaluation schedule to allow 14 days prior to study dosing. Reduction in frequency and intensity of follow-up evaluations. Standardization of study endpoints. Inclusion of toxicity scoring and management for amylase and triglyceride elevations. Clarification of concomitant medication use. Original design: To determine the effectiveness of didanosine (ddI) in patients with AIDS or advanced AIDS related complex (ARC) who have documented hematologic intolerance to zidovudine (AZT) therapy. To determine if the efficacy of ddI increases with increasing doses.

AZT is effective in reducing mortality in patients with AIDS who receive the drug after the first episode of Pneumocystis carinii pneumonia (PCP) and in patients with advanced ARC. However, AZT therapy has been associated with significant toxicities. In addition, the effectiveness of AZT appears to decrease during the second and third years of therapy. For these reasons, the development of alternative therapy that would be at least as effective but less toxic is of great importance. The drug ddI is an antiviral agent that inhibits replication (reproduction) of HIV with less apparent toxicity than AZT. The major dose-limiting toxicities found in the Phase I studies have been pains in the feet and legs of 2 patients initially receiving 12 mg/kg/day and 12 patients receiving daily doses of 25.8 to 51.2 mg/kg; symptoms began 8 to 27 weeks after initiating ddI treatment. These neuropathy-like symptoms have generally not been associated with significant abnormalities in nerve conduction studies and patients have reported marked improvement in symptoms within 1 to 2 weeks of discontinuing ddI. Some patients have resumed ddI treatment at a reduced dose after resolution of their symptoms. Studies indicate that ddI remains active in the body for at least 12 hours. This indicates that benefits of ddI might be achieved with a low frequency of drug administration.

Visão geral do estudo

Status

Concluído

Condições

Infecções por HIV

Intervenção / Tratamento

Medicamento: Didanosina

Descrição detalhada

Patients are randomized to one of three ddI treatment groups; within each group, doses will be adjusted according to patient's weight at study entry. Stratification is by diagnosis of AIDS or AIDS related complex (ARC) and Medical Center. Data will be tabulated for the Data and Safety Monitoring Board at 3 month intervals.

Tipo de estudo

Intervencional

Inscrição

660

Estágio

Fase 2

Contactos e Locais

Esta seção fornece os detalhes de contato para aqueles que conduzem o estudo e informações sobre onde este estudo está sendo realizado.

Locais de estudo

Estados Unidos
- California
  - Los Angeles, California, Estados Unidos, 90033
    - Los Angeles County - USC Med Ctr
  - Los Angeles, California, Estados Unidos, 900481804
    - Cedars Sinai / UCLA Med Ctr
  - Los Angeles, California, Estados Unidos, 905022004
    - Harbor - UCLA Med Ctr / UCLA School of Medicine
  - Los Angeles, California, Estados Unidos, 900951752
    - UCLA Med Ctr / Pediatric
  - Palo Alto, California, Estados Unidos, 94304
    - Palo Alto Veterans Adm Med Ctr / Stanford Univ
  - San Diego, California, Estados Unidos, 921036325
    - Univ of California / San Diego Treatment Ctr
  - Stanford, California, Estados Unidos, 94305
    - Stanford Univ School of Medicine
  - Sylmar, California, Estados Unidos, 91342
    - Olive View Med Ctr
  - Sylmar, California, Estados Unidos, 91342
    - Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr
  - Torrance, California, Estados Unidos, 90502
    - Harbor UCLA Med Ctr
- Colorado
  - Denver, Colorado, Estados Unidos, 80262
    - Univ of Colorado Health Sciences Ctr
  - Denver, Colorado, Estados Unidos, 80262
    - Mountain States Regional Hemophilia Ctr / Univ of Colorado
- District of Columbia
  - Washington, District of Columbia, Estados Unidos, 20037
    - George Washington Univ Med Ctr
- Florida
  - Fort Lauderdale, Florida, Estados Unidos, 33316
    - G E Morey Jr
  - Miami, Florida, Estados Unidos, 331361013
    - Univ of Miami School of Medicine
  - Tampa, Florida, Estados Unidos, 33612
    - Univ of South Florida
- Illinois
  - Chicago, Illinois, Estados Unidos, 60611
    - Northwestern Univ Med School
  - Hines, Illinois, Estados Unidos, 60141
    - Edward Hines Veterans Administration Hosp
- Indiana
  - Indianapolis, Indiana, Estados Unidos, 462025250
    - Indiana Univ Hosp
- Kansas
  - Wichita, Kansas, Estados Unidos, 67214
    - Univ of Kansas School of Medicine
- Louisiana
  - New Orleans, Louisiana, Estados Unidos, 70112
    - Louisiana Comprehensive Hemophilia Care Ctr
  - New Orleans, Louisiana, Estados Unidos, 70112
    - Louisiana State Univ Med Ctr / Tulane Med School
  - New Orleans, Louisiana, Estados Unidos, 70112
    - Tulane Univ School of Medicine
- Maryland
  - Baltimore, Maryland, Estados Unidos, 21287
    - Johns Hopkins Hosp
- Massachusetts
  - Boston, Massachusetts, Estados Unidos, 02114
    - Harvard (Massachusetts Gen Hosp)
  - Boston, Massachusetts, Estados Unidos, 02118
    - Boston Med Ctr
  - Boston, Massachusetts, Estados Unidos, 02215
    - Beth Israel Deaconess - West Campus
  - Boston, Massachusetts, Estados Unidos, 02215
    - Beth Israel Deaconess Med Ctr
  - Springfield, Massachusetts, Estados Unidos, 01199
    - Baystate Med Ctr of Springfield
  - Worcester, Massachusetts, Estados Unidos, 01605
    - Med Ctr of Central Massachusetts
  - Worcester, Massachusetts, Estados Unidos, 01655
    - Univ of Massachusetts Med Ctr
- Minnesota
  - Minneapolis, Minnesota, Estados Unidos, 55455
    - Univ of Minnesota
- Nebraska
  - Omaha, Nebraska, Estados Unidos, 68105
    - Nebraska Regional Hemophilia Ctr
- New York
  - Bronx, New York, Estados Unidos, 10461
    - Bronx Municipal Hosp Ctr/Jacobi Med Ctr
  - Bronx, New York, Estados Unidos, 10465
    - Jack Weiler Hosp / Bronx Municipal Hosp
  - Bronx, New York, Estados Unidos, 10467
    - Montefiore Med Ctr / Bronx Municipal Hosp
  - Bronx, New York, Estados Unidos, 10468
    - Bronx Veterans Administration / Mount Sinai Hosp
  - Buffalo, New York, Estados Unidos, 14215
    - SUNY / Erie County Med Ctr at Buffalo
  - Elmhurst, New York, Estados Unidos, 11373
    - City Hosp Ctr at Elmhurst / Mount Sinai Hosp
  - New York, New York, Estados Unidos, 10003
    - Beth Israel Med Ctr / Peter Krueger Clinic
  - New York, New York, Estados Unidos, 10016
    - Bellevue Hosp / New York Univ Med Ctr
  - New York, New York, Estados Unidos, 10021
    - Mem Sloan - Kettering Cancer Ctr
  - New York, New York, Estados Unidos, 10025
    - Saint Luke's - Roosevelt Hosp Ctr
  - New York, New York, Estados Unidos, 10029
    - Mount Sinai Hemophilia Ctr / Mount Sinai Med Ctr
  - New York, New York, Estados Unidos, 10029
    - Mount Sinai Med Ctr
  - Rochester, New York, Estados Unidos, 14642
    - Univ of Rochester Medical Center
  - Stony Brook, New York, Estados Unidos, 117948153
    - SUNY - Stony Brook
  - Syracuse, New York, Estados Unidos, 13210
    - SUNY / State Univ of New York
- North Carolina
  - Chapel Hill, North Carolina, Estados Unidos, 275997215
    - Univ of North Carolina
  - Durham, North Carolina, Estados Unidos, 27710
    - Duke Univ Med Ctr
  - Winston-Salem, North Carolina, Estados Unidos, 27103
    - Bowman Gray School of Medicine / Wake Forest Univ
- Ohio
  - Cincinnati, Ohio, Estados Unidos, 452670405
    - Holmes Hosp / Univ of Cincinnati Med Ctr
  - Cleveland, Ohio, Estados Unidos, 44106
    - Univ Hosp of Cleveland / Case Western Reserve Univ
  - Columbus, Ohio, Estados Unidos, 432101228
    - Ohio State Univ Hosp Clinic
- Pennsylvania
  - Hershey, Pennsylvania, Estados Unidos, 170330850
    - Milton S Hershey Med Ctr
  - Philadelphia, Pennsylvania, Estados Unidos, 19104
    - Univ of Pennsylvania
  - Pittsburgh, Pennsylvania, Estados Unidos, 15219
    - Hemophilia Ctr of Western PA / Univ of Pittsburgh
  - Pittsburgh, Pennsylvania, Estados Unidos
    - Univ of Pittsburgh Med School
- South Carolina
  - West Columbia, South Carolina, Estados Unidos, 29169
    - Julio Arroyo
- Tennessee
  - Knoxville, Tennessee, Estados Unidos, 37920
    - Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
- Texas
  - Galveston, Texas, Estados Unidos, 77550
    - Univ TX Galveston Med Branch
  - Houston, Texas, Estados Unidos, 77030
    - Hermann Hosp / Univ Texas Health Science Ctr
  - Houston, Texas, Estados Unidos, 77030
    - Texas Children's Hosp / Baylor Univ
- Utah
  - Salt Lake City, Utah, Estados Unidos, 84132
    - Univ of Utah School of Medicine
- Washington
  - Seattle, Washington, Estados Unidos, 98105
    - Univ of Washington
- Wisconsin
  - Milwaukee, Wisconsin, Estados Unidos, 53233
    - Great Lakes Hemophilia Foundation
Porto Rico
- - San Juan, Porto Rico, 009275800
    - San Juan Veterans Administration Med Ctr

Critérios de participação

Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.

Critérios de elegibilidade

Idades elegíveis para estudo

12 anos e mais velhos (Filho, Adulto, Adulto mais velho)

Aceita Voluntários Saudáveis

Não

Gêneros Elegíveis para o Estudo

Tudo

Descrição

Inclusion Criteria

Concurrent Medication:

Required:

Aerosolized pentamidine (300 mg every 4 weeks). In the event of physiological intolerance, alternative PCP prophylaxis may be trimethoprim/sulfamethoxazole 1 DS tab per day or dapsone 50 - 100 mg per day.

Allowed:

Chronic suppressive treatment for toxoplasmosis, Pneumocystis carinii pneumonia (PCP), cryptococcal meningitis, herpes simplex virus, cytomegalovirus, coccidioidomycosis, and histoplasmosis (absorption of ketoconazole or dapsone may be inhibited if given at the same time as the buffered solution of ddI, and should be taken 2 hours before or 2 hours after taking ddI; oral acidifying agents are not allowed). Isoniazid is permitted only if no acceptable alternative therapy is available. Metronidazole may be used for single courses not to exceed 14 days within consecutive 90 day intervals, the first of which begins at the initiation of the study. Erythropoietin for patients under the relevant treatment IND. Intravenous acyclovir for short courses of therapy.

Patients must:

Have documented hematologic intolerance to zidovudine (AZT).
Have the diagnosis of AIDS or advanced AIDS related complex (ARC).
Have ended treatment for acute Pneumocystis carinii pneumonia (PCP) at least 2 weeks before study entry.

Have previous intolerance on at least two courses of AZT therapy (one of which must have been at daily doses of 500 mg of AZT or less).

Be able to provide informed consent (and/or guardian as appropriate).
Be available for follow-up for at least 6 months.
Have baseline laboratory values as measured within 7 days before initial drug dosing.
Allowed:
Development of new opportunistic infections during the study - patients remain in the protocol.

Prior Medication:

Required:

Prior use and intolerance to zidovudine (AZT).
Allowed:
Intralesional agents.

Exclusion Criteria

Co-existing Condition:

Patients with the following are excluded:

Presence of Kaposi's sarcoma (KS) with known or suspected visceral disease or where KS requires chemotherapy.
Active AIDS defining opportunistic infections not specifically allowed.
Intractable diarrhea.
Stage 2 AIDS-dementia complex.
History of intolerance to aerosolized pentamidine.
Grade 2 neuropathy, based on the Neuropathy Targeted Symptom Questionnaire, or any moderate abnormality indicative of peripheral neuropathy, particularly impaired sensation of sharp pain, light touch, or vibration in the lower extremities, distal extremity weakness, or distal extremity hyporeflexia.
Prior history of acute or chronic pancreatitis.
History of seizures within past 2 years or currently requiring anticonvulsants for control.
Any other clinical conditions or prior therapy which, in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing requirements.

Concurrent Medication:

Excluded:

Isoniazid (INH).

Patients with the following are excluded:

Active AIDS-defining opportunistic infections not specifically allowed.
Intractable diarrhea.
AIDS-dementia complex = or > stage 2.
History of intolerance to aerosolized pentamidine. Grade 2 neuropathy, based on the Neuropathy Targeted Symptom Questionnaire, or any moderate abnormality indicative of peripheral neuropathy, particularly impaired sensation of sharp pain, light touch, or vibration in the lower extremities, distal extremity weakness, or distal extremity hyporeflexia.
Prior history of acute or chronic pancreatitis.
History of seizures within past 2 years or currently requiring anticonvulsants for control.
Any other clinical conditions or prior therapy which, in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing requirements.
Previous participation in any Phase I ddI study.
Life expectancy < 6 months.

Prior Medication:

Excluded:

Chronic therapy for cytomegalovirus infection with ganciclovir.
ddI.
d4T.
ddC.

Excluded within 2 weeks of study entry:

Zidovudine (AZT).

Excluded within 1 month of study entry:

Therapy with any other antiretroviral drug or investigational agent not specifically allowed, including interferon and immunomodulating drugs.
Ganciclovir.
Neurotoxic drugs.

Excluded within 3 months of study entry:

Ribavirin.
Cytotoxic anticancer therapy.

Prior Treatment:

Excluded within 2 weeks of study randomization:

Transfusion.

Active alcohol or drug abuse that is sufficient, in investigator's opinion, to prevent adequate compliance with study therapy.

Plano de estudo

Esta seção fornece detalhes do plano de estudo, incluindo como o estudo é projetado e o que o estudo está medindo.

Como o estudo é projetado?

Detalhes do projeto

Finalidade Principal: Tratamento

Colaboradores e Investigadores

É aqui que você encontrará pessoas e organizações envolvidas com este estudo.

Patrocinador

National Institute of Allergy and Infectious Diseases (NIAID)

Colaboradores

Bristol-Myers Squibb

Investigadores

Cadeira de estudo: JD Allan
Cadeira de estudo: J Groopman
Cadeira de estudo: M Seidlin

Publicações e links úteis

A pessoa responsável por inserir informações sobre o estudo fornece voluntariamente essas publicações. Estes podem ser sobre qualquer coisa relacionada ao estudo.

Publicações Gerais

Bozzette SA, Hays RD, Berry SH, Kanouse DE. A Perceived Health Index for use in persons with advanced HIV disease: derivation, reliability, and validity. Med Care. 1994 Jul;32(7):716-31. doi: 10.1097/00005650-199407000-00005.
Fiscus SA, Heggem-Snow A, Troiani L, Wallmark E, Folds JD, Sheff B, van der Horst CM. Transient high titers of HIV-1 in plasma and progression of disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 May 1;9(1):51-7.
Kozal MJ, Kroodsma K, Winters MA, Shafer RW, Efron B, Katzenstein DA, Merigan TC. Didanosine resistance in HIV-infected patients switched from zidovudine to didanosine monotherapy. Ann Intern Med. 1994 Aug 15;121(4):263-8. doi: 10.7326/0003-4819-121-4-199408150-00005.
Fichtenbaum CJ, Clifford DB, Powderly WG. Risk factors for dideoxynucleoside-induced toxic neuropathy in patients with the human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Oct 1;10(2):169-74. doi: 10.1097/00042560-199510020-00009.
Spino C, Kahn JO, Dolin R, Phair JP. Predictors of survival in HIV-infected persons with 50 or fewer CD4 cells/mm3. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Aug 15;15(5):346-55. doi: 10.1097/00042560-199708150-00004.
Reddy MM, Winger EE, Hargrove D, McHugh T, McKinley GF, Grieco MH. An improved method for monitoring efficacy of anti-retroviral therapy in HIV-infected individuals: a highly sensitive HIV p24 antigen assay. J Clin Lab Anal. 1992;6(3):125-9. doi: 10.1002/jcla.1860060305.
Grieco MH, McKinley GF, Reddy MM. Effect of 2',3',-dideoxyinosine on HIV P24 antigen, beta2-microglobulin, neopterin,SCD8,SCD4,and SIL2R levels in patients with ARC or AIDS. Int Conf AIDS. 1991 Jun 16-21;7(2):199 (abstract no WB2069)
Allan JD, DeGruttola V, Cross A, McLaren C, Seidlin M, Pettinelli C. An efficacy study of 2'3'-dideoxyinosine [ddI](BMY-40900) administered orally twice daily to zidovudine intolerant patients with HIV infection (ACTG 118). The AIDS Clinical Trials Group. Int Conf AIDS. 1993 Jun 6-11;9(1):67 (abstract no WS-B24-2)
Sharma PL, Chatis PA, Dogon AL, Mayers DL, McCutchan FE, Page C, Crumpacker CS. AZT-related mutation Lys70Arg in reverse transcriptase of human immunodeficiency virus type 1 confers decrease in susceptibility to ddATP in in vitro RT inhibition assay. Virology. 1996 Sep 15;223(2):365-9. doi: 10.1006/viro.1996.0488. Erratum In: Virology 1996 Nov 15;225(2):428.

Datas de registro do estudo

Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.

Datas Principais do Estudo

Conclusão Primária (Real)

1 de fevereiro de 1993

Datas de inscrição no estudo

Enviado pela primeira vez

2 de novembro de 1999

Enviado pela primeira vez que atendeu aos critérios de CQ

30 de agosto de 2001

Primeira postagem (Estimativa)

31 de agosto de 2001

Atualizações de registro de estudo

Última Atualização Postada (Estimativa)

14 de março de 2011

Última atualização enviada que atendeu aos critérios de controle de qualidade

11 de março de 2011

Última verificação

1 de outubro de 1994

Mais Informações

Termos relacionados a este estudo

Palavras-chave

Termos MeSH relevantes adicionais

Outros números de identificação do estudo

ACTG 118
070V1
AI454-007

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