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

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00000672
• Other study ID #: ACTG 118
• Secondary ID: 070V1AI454-007
• Status: Completed
• Phase: Phase 2
• First received: November 2, 1999
• Last updated: March 11, 2011

Study information

• Verified date: October 1994
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 660
• Est. primary completion date: February 1993
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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.

Study Design

Primary Purpose: Treatment

Related Conditions & MeSH terms

• AIDS-Related Complex
• HIV Infections

Intervention

Drug:
• Didanosine

Locations

Country	Name	City	State
Puerto Rico	San Juan Veterans Administration Med Ctr	San Juan
United States	Johns Hopkins Hosp	Baltimore	Maryland
United States	Beth Israel Deaconess - West Campus	Boston	Massachusetts
United States	Beth Israel Deaconess Med Ctr	Boston	Massachusetts
United States	Boston Med Ctr	Boston	Massachusetts
United States	Harvard (Massachusetts Gen Hosp)	Boston	Massachusetts
United States	Bronx Municipal Hosp Ctr/Jacobi Med Ctr	Bronx	New York
United States	Bronx Veterans Administration / Mount Sinai Hosp	Bronx	New York
United States	Jack Weiler Hosp / Bronx Municipal Hosp	Bronx	New York
United States	Montefiore Med Ctr / Bronx Municipal Hosp	Bronx	New York
United States	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York
United States	Univ of North Carolina	Chapel Hill	North Carolina
United States	Northwestern Univ Med School	Chicago	Illinois
United States	Holmes Hosp / Univ of Cincinnati Med Ctr	Cincinnati	Ohio
United States	Univ Hosp of Cleveland / Case Western Reserve Univ	Cleveland	Ohio
United States	Ohio State Univ Hosp Clinic	Columbus	Ohio
United States	Mountain States Regional Hemophilia Ctr / Univ of Colorado	Denver	Colorado
United States	Univ of Colorado Health Sciences Ctr	Denver	Colorado
United States	Duke Univ Med Ctr	Durham	North Carolina
United States	City Hosp Ctr at Elmhurst / Mount Sinai Hosp	Elmhurst	New York
United States	G E Morey Jr	Fort Lauderdale	Florida
United States	Univ TX Galveston Med Branch	Galveston	Texas
United States	Milton S Hershey Med Ctr	Hershey	Pennsylvania
United States	Edward Hines Veterans Administration Hosp	Hines	Illinois
United States	Hermann Hosp / Univ Texas Health Science Ctr	Houston	Texas
United States	Texas Children's Hosp / Baylor Univ	Houston	Texas
United States	Indiana Univ Hosp	Indianapolis	Indiana
United States	Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr	Knoxville	Tennessee
United States	Cedars Sinai / UCLA Med Ctr	Los Angeles	California
United States	Harbor - UCLA Med Ctr / UCLA School of Medicine	Los Angeles	California
United States	Los Angeles County - USC Med Ctr	Los Angeles	California
United States	UCLA Med Ctr / Pediatric	Los Angeles	California
United States	Univ of Miami School of Medicine	Miami	Florida
United States	Great Lakes Hemophilia Foundation	Milwaukee	Wisconsin
United States	Univ of Minnesota	Minneapolis	Minnesota
United States	Louisiana Comprehensive Hemophilia Care Ctr	New Orleans	Louisiana
United States	Louisiana State Univ Med Ctr / Tulane Med School	New Orleans	Louisiana
United States	Tulane Univ School of Medicine	New Orleans	Louisiana
United States	Bellevue Hosp / New York Univ Med Ctr	New York	New York
United States	Beth Israel Med Ctr / Peter Krueger Clinic	New York	New York
United States	Mem Sloan - Kettering Cancer Ctr	New York	New York
United States	Mount Sinai Hemophilia Ctr / Mount Sinai Med Ctr	New York	New York
United States	Mount Sinai Med Ctr	New York	New York
United States	Saint Luke's - Roosevelt Hosp Ctr	New York	New York
United States	Nebraska Regional Hemophilia Ctr	Omaha	Nebraska
United States	Palo Alto Veterans Adm Med Ctr / Stanford Univ	Palo Alto	California
United States	Univ of Pennsylvania	Philadelphia	Pennsylvania
United States	Hemophilia Ctr of Western PA / Univ of Pittsburgh	Pittsburgh	Pennsylvania
United States	Univ of Pittsburgh Med School	Pittsburgh	Pennsylvania
United States	Univ of Rochester Medical Center	Rochester	New York
United States	Univ of Utah School of Medicine	Salt Lake City	Utah
United States	Univ of California / San Diego Treatment Ctr	San Diego	California
United States	Univ of Washington	Seattle	Washington
United States	Baystate Med Ctr of Springfield	Springfield	Massachusetts
United States	Stanford Univ School of Medicine	Stanford	California
United States	SUNY - Stony Brook	Stony Brook	New York
United States	Olive View Med Ctr	Sylmar	California
United States	Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr	Sylmar	California
United States	SUNY / State Univ of New York	Syracuse	New York
United States	Univ of South Florida	Tampa	Florida
United States	Harbor UCLA Med Ctr	Torrance	California
United States	George Washington Univ Med Ctr	Washington	District of Columbia
United States	Julio Arroyo	West Columbia	South Carolina
United States	Univ of Kansas School of Medicine	Wichita	Kansas
United States	Bowman Gray School of Medicine / Wake Forest Univ	Winston-Salem	North Carolina
United States	Med Ctr of Central Massachusetts	Worcester	Massachusetts
United States	Univ of Massachusetts Med Ctr	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (10)

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)

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. — View Citation

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. — View Citation

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. — View Citation

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)

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. — View Citation

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. — View Citation

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. Erratum in: Virology 1996 Nov 15;225(2):428. — View Citation

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. — View Citation

Winger EE, Reddy MM, Hargrove D, McHugh T, McKinley GF, Grieco MH. A sensitive method for monitoring efficacy of anti-retroviral therapy in HIV-infected individuals: a highly sensitive p24 antigen assay. Int Conf AIDS. 1991 Jun 16-21;7(1):31 (abstract no MB38)

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