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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 maart 2011 bijgewerkt door: 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.

Studie Overzicht

Toestand

Voltooid

Conditie

HIV-infecties

Interventie / Behandeling

Geneesmiddel: Didanosine

Gedetailleerde beschrijving

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.

Studietype

Ingrijpend

Inschrijving

660

Fase

Fase 2

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

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

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

12 jaar en ouder (Kind, Volwassen, Oudere volwassene)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

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.

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Primair doel: Behandeling

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Medewerkers

Bristol-Myers Squibb

Onderzoekers

Studie stoel: JD Allan
Studie stoel: J Groopman
Studie stoel: M Seidlin

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Algemene publicaties

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.

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Primaire voltooiing (Werkelijk)

1 februari 1993

Studieregistratiedata

Eerst ingediend

2 november 1999

Eerst ingediend dat voldeed aan de QC-criteria

30 augustus 2001

Eerst geplaatst (Schatting)

31 augustus 2001

Updates van studierecords

Laatste update geplaatst (Schatting)

14 maart 2011

Laatste update ingediend die voldeed aan QC-criteria

11 maart 2011

Laatst geverifieerd

1 oktober 1994

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

ACTG 118
070V1
AI454-007

Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .