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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 mars 2011 mis à jour par: 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.

Aperçu de l'étude

Statut

Complété

Les conditions

Infections à VIH

Intervention / Traitement

Médicament: Didanosine

Description détaillée

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.

Type d'étude

Interventionnel

Inscription

660

Phase

Phase 2

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

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

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

12 ans et plus (Enfant, Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

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.

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

Objectif principal: Traitement

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborateurs

Bristol-Myers Squibb

Les enquêteurs

Chaise d'étude: JD Allan
Chaise d'étude: J Groopman
Chaise d'étude: M Seidlin

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Publications générales

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.

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Achèvement primaire (Réel)

1 février 1993

Dates d'inscription aux études

Première soumission

2 novembre 1999

Première soumission répondant aux critères de contrôle qualité

30 août 2001

Première publication (Estimation)

31 août 2001

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Estimation)

14 mars 2011

Dernière mise à jour soumise répondant aux critères de contrôle qualité

11 mars 2011

Dernière vérification

1 octobre 1994

Plus d'information

Termes liés à cette étude

Mots clés

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

ACTG 118
070V1
AI454-007

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .