- ICH GCP
- US Clinical Trials Registry
- Klinisk forsøg NCT00000672
An Efficacy Study of 2',3'-Dideoxyinosine (ddI) (BMY-40900) Administered Orally Twice Daily to Zidovudine Intolerant Patients With AIDS or AIDS-Related Complex
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.
Studieoversigt
Detaljeret beskrivelse
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.
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.
Undersøgelsestype
Tilmelding
Fase
- Fase 2
Kontakter og lokationer
Studiesteder
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California
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Los Angeles, California, Forenede Stater, 90033
- Los Angeles County - USC Med Ctr
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Los Angeles, California, Forenede Stater, 900481804
- Cedars Sinai / UCLA Med Ctr
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Los Angeles, California, Forenede Stater, 905022004
- Harbor - UCLA Med Ctr / UCLA School of Medicine
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Los Angeles, California, Forenede Stater, 900951752
- UCLA Med Ctr / Pediatric
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Palo Alto, California, Forenede Stater, 94304
- Palo Alto Veterans Adm Med Ctr / Stanford Univ
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San Diego, California, Forenede Stater, 921036325
- Univ of California / San Diego Treatment Ctr
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Stanford, California, Forenede Stater, 94305
- Stanford Univ School of Medicine
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Sylmar, California, Forenede Stater, 91342
- Olive View Med Ctr
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Sylmar, California, Forenede Stater, 91342
- Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr
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Torrance, California, Forenede Stater, 90502
- Harbor UCLA Med Ctr
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Colorado
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Denver, Colorado, Forenede Stater, 80262
- Univ of Colorado Health Sciences Ctr
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Denver, Colorado, Forenede Stater, 80262
- Mountain States Regional Hemophilia Ctr / Univ of Colorado
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District of Columbia
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Washington, District of Columbia, Forenede Stater, 20037
- George Washington Univ Med Ctr
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Florida
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Fort Lauderdale, Florida, Forenede Stater, 33316
- G E Morey Jr
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Miami, Florida, Forenede Stater, 331361013
- Univ of Miami School of Medicine
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Tampa, Florida, Forenede Stater, 33612
- Univ of South Florida
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Illinois
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Chicago, Illinois, Forenede Stater, 60611
- Northwestern Univ Med School
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Hines, Illinois, Forenede Stater, 60141
- Edward Hines Veterans Administration Hosp
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Indiana
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Indianapolis, Indiana, Forenede Stater, 462025250
- Indiana Univ Hosp
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Kansas
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Wichita, Kansas, Forenede Stater, 67214
- Univ of Kansas School of Medicine
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Louisiana
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New Orleans, Louisiana, Forenede Stater, 70112
- Louisiana Comprehensive Hemophilia Care Ctr
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New Orleans, Louisiana, Forenede Stater, 70112
- Louisiana State Univ Med Ctr / Tulane Med School
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New Orleans, Louisiana, Forenede Stater, 70112
- Tulane Univ School of Medicine
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Maryland
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Baltimore, Maryland, Forenede Stater, 21287
- Johns Hopkins Hosp
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Massachusetts
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Boston, Massachusetts, Forenede Stater, 02114
- Harvard (Massachusetts Gen Hosp)
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Boston, Massachusetts, Forenede Stater, 02118
- Boston Med Ctr
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Boston, Massachusetts, Forenede Stater, 02215
- Beth Israel Deaconess - West Campus
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Boston, Massachusetts, Forenede Stater, 02215
- Beth Israel Deaconess Med Ctr
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Springfield, Massachusetts, Forenede Stater, 01199
- Baystate Med Ctr of Springfield
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Worcester, Massachusetts, Forenede Stater, 01605
- Med Ctr of Central Massachusetts
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Worcester, Massachusetts, Forenede Stater, 01655
- Univ of Massachusetts Med Ctr
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Minnesota
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Minneapolis, Minnesota, Forenede Stater, 55455
- Univ of Minnesota
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Nebraska
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Omaha, Nebraska, Forenede Stater, 68105
- Nebraska Regional Hemophilia Ctr
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New York
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Bronx, New York, Forenede Stater, 10461
- Bronx Municipal Hosp Ctr/Jacobi Med Ctr
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Bronx, New York, Forenede Stater, 10465
- Jack Weiler Hosp / Bronx Municipal Hosp
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Bronx, New York, Forenede Stater, 10467
- Montefiore Med Ctr / Bronx Municipal Hosp
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Bronx, New York, Forenede Stater, 10468
- Bronx Veterans Administration / Mount Sinai Hosp
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Buffalo, New York, Forenede Stater, 14215
- SUNY / Erie County Med Ctr at Buffalo
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Elmhurst, New York, Forenede Stater, 11373
- City Hosp Ctr at Elmhurst / Mount Sinai Hosp
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New York, New York, Forenede Stater, 10003
- Beth Israel Med Ctr / Peter Krueger Clinic
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New York, New York, Forenede Stater, 10016
- Bellevue Hosp / New York Univ Med Ctr
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New York, New York, Forenede Stater, 10021
- Mem Sloan - Kettering Cancer Ctr
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New York, New York, Forenede Stater, 10025
- Saint Luke's - Roosevelt Hosp Ctr
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New York, New York, Forenede Stater, 10029
- Mount Sinai Hemophilia Ctr / Mount Sinai Med Ctr
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New York, New York, Forenede Stater, 10029
- Mount Sinai Med Ctr
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Rochester, New York, Forenede Stater, 14642
- Univ of Rochester Medical Center
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Stony Brook, New York, Forenede Stater, 117948153
- SUNY - Stony Brook
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Syracuse, New York, Forenede Stater, 13210
- SUNY / State Univ of New York
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North Carolina
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Chapel Hill, North Carolina, Forenede Stater, 275997215
- Univ of North Carolina
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Durham, North Carolina, Forenede Stater, 27710
- Duke Univ Med Ctr
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Winston-Salem, North Carolina, Forenede Stater, 27103
- Bowman Gray School of Medicine / Wake Forest Univ
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Ohio
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Cincinnati, Ohio, Forenede Stater, 452670405
- Holmes Hosp / Univ of Cincinnati Med Ctr
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Cleveland, Ohio, Forenede Stater, 44106
- Univ Hosp of Cleveland / Case Western Reserve Univ
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Columbus, Ohio, Forenede Stater, 432101228
- Ohio State Univ Hosp Clinic
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Pennsylvania
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Hershey, Pennsylvania, Forenede Stater, 170330850
- Milton S Hershey Med Ctr
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Philadelphia, Pennsylvania, Forenede Stater, 19104
- Univ of Pennsylvania
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Pittsburgh, Pennsylvania, Forenede Stater, 15219
- Hemophilia Ctr of Western PA / Univ of Pittsburgh
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Pittsburgh, Pennsylvania, Forenede Stater
- Univ of Pittsburgh Med School
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South Carolina
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West Columbia, South Carolina, Forenede Stater, 29169
- Julio Arroyo
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Tennessee
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Knoxville, Tennessee, Forenede Stater, 37920
- Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
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Texas
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Galveston, Texas, Forenede Stater, 77550
- Univ TX Galveston Med Branch
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Houston, Texas, Forenede Stater, 77030
- Hermann Hosp / Univ Texas Health Science Ctr
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Houston, Texas, Forenede Stater, 77030
- Texas Children's Hosp / Baylor Univ
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Utah
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Salt Lake City, Utah, Forenede Stater, 84132
- Univ of Utah School of Medicine
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Washington
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Seattle, Washington, Forenede Stater, 98105
- Univ of Washington
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Wisconsin
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Milwaukee, Wisconsin, Forenede Stater, 53233
- Great Lakes Hemophilia Foundation
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San Juan, Puerto Rico, 009275800
- San Juan Veterans Administration Med Ctr
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Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Beskrivelse
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.
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Behandling
Samarbejdspartnere og efterforskere
Samarbejdspartnere
Efterforskere
- Studiestol: JD Allan
- Studiestol: J Groopman
- Studiestol: M Seidlin
Publikationer og nyttige links
Generelle publikationer
- 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.
Datoer for undersøgelser
Studer store datoer
Primær færdiggørelse (Faktiske)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Skøn)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Skøn)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Yderligere relevante MeSH-vilkår
- RNA-virusinfektioner
- Virussygdomme
- Infektioner
- Blodbårne infektioner
- Overførbare sygdomme
- Seksuelt overførte sygdomme, virale
- Seksuelt overførte sygdomme
- Lentivirus infektioner
- Retroviridae infektioner
- Immunologiske mangelsyndromer
- Sygdomme i immunsystemet
- Langsomme virussygdomme
- HIV-infektioner
- AIDS-relateret kompleks
- Molekylære mekanismer for farmakologisk virkning
- Anti-infektionsmidler
- Antivirale midler
- Reverse transkriptasehæmmere
- Nukleinsyresyntesehæmmere
- Enzymhæmmere
- Anti-HIV-midler
- Anti-retrovirale midler
- Antimetabolitter
- Didanosin
Andre undersøgelses-id-numre
- ACTG 118
- 070V1
- AI454-007
Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .
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