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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


Phase 2
12 Years
N/A
Not Enrolling
Both
HIV Infections

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Trial Information

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


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.

Inclusion Criteria


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.

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

JD Allan

Investigator Role:

Study Chair

Authority:

United States: Federal Government

Study ID:

ACTG 118

NCT ID:

NCT00000672

Start Date:

Completion Date:

Related Keywords:

  • HIV Infections
  • Didanosine
  • Zidovudine
  • HIV Infections
  • Acquired Immunodeficiency Syndrome
  • AIDS-Related Complex

Name

Location

Bellevue Hosp / New York Univ Med CtrNew York, New York  10016
Mem Sloan - Kettering Cancer CtrNew York, New York  10021
Saint Luke's - Roosevelt Hosp CtrNew York, New York  10025
Univ of Rochester Medical CenterRochester, New York  14642
Julio ArroyoWest Columbia, South Carolina  29169
Los Angeles County - USC Med CtrLos Angeles, California  90033
Cedars Sinai / UCLA Med CtrLos Angeles, California  900481804
Harbor - UCLA Med Ctr / UCLA School of MedicineLos Angeles, California  905022004
Palo Alto Veterans Adm Med Ctr / Stanford UnivPalo Alto, California  94304
Univ of California / San Diego Treatment CtrSan Diego, California  921036325
Stanford Univ School of MedicineStanford, California  94305
Sepulveda Veterans Adm Med Ctr / Olive View Med CtrSylmar, California  91342
Olive View Med CtrSylmar, California  91342
Harbor UCLA Med CtrTorrance, California  90502
Univ of Colorado Health Sciences CtrDenver, Colorado  80262
Mountain States Regional Hemophilia Ctr / Univ of ColoradoDenver, Colorado  80262
George Washington Univ Med CtrWashington, District of Columbia  20037
G E Morey JrFort Lauderdale, Florida  33316
Univ of Miami School of MedicineMiami, Florida  331361013
Northwestern Univ Med SchoolChicago, Illinois  60611
Edward Hines Veterans Administration HospHines, Illinois  60141
Indiana Univ HospIndianapolis, Indiana  462025250
Univ of Kansas School of MedicineWichita, Kansas  67214
Louisiana State Univ Med Ctr / Tulane Med SchoolNew Orleans, Louisiana  70112
Tulane Univ School of MedicineNew Orleans, Louisiana  70112
Louisiana Comprehensive Hemophilia Care CtrNew Orleans, Louisiana  70112
Harvard (Massachusetts Gen Hosp)Boston, Massachusetts  02114
Beth Israel Deaconess Med CtrBoston, Massachusetts  02215
Beth Israel Deaconess - West CampusBoston, Massachusetts  02215
Boston Med CtrBoston, Massachusetts  02118
Baystate Med Ctr of SpringfieldSpringfield, Massachusetts  01199
Univ of Massachusetts Med CtrWorcester, Massachusetts  01655
Med Ctr of Central MassachusettsWorcester, Massachusetts  01605
Univ of MinnesotaMinneapolis, Minnesota  55455
Nebraska Regional Hemophilia CtrOmaha, Nebraska  68105
Bronx Municipal Hosp Ctr/Jacobi Med CtrBronx, New York  10461
Jack Weiler Hosp / Bronx Municipal HospBronx, New York  10465
Bronx Veterans Administration / Mount Sinai HospBronx, New York  10468
Montefiore Med Ctr / Bronx Municipal HospBronx, New York  10467
SUNY / Erie County Med Ctr at BuffaloBuffalo, New York  14215
City Hosp Ctr at Elmhurst / Mount Sinai HospElmhurst, New York  11373
Mount Sinai Hemophilia Ctr / Mount Sinai Med CtrNew York, New York  10029
Mount Sinai Med CtrNew York, New York  10029
Beth Israel Med Ctr / Peter Krueger ClinicNew York, New York  10003
SUNY - Stony BrookStony Brook, New York  117948153
SUNY / State Univ of New YorkSyracuse, New York  13210
Univ of North CarolinaChapel Hill, North Carolina  275997215
Duke Univ Med CtrDurham, North Carolina  27710
Bowman Gray School of Medicine / Wake Forest UnivWinston-Salem, North Carolina  27103
Holmes Hosp / Univ of Cincinnati Med CtrCincinnati, Ohio  452670405
Univ Hosp of Cleveland / Case Western Reserve UnivCleveland, Ohio  44106
Ohio State Univ Hosp ClinicColumbus, Ohio  432101228
Milton S Hershey Med CtrHershey, Pennsylvania  170330850
Univ of PennsylvaniaPhiladelphia, Pennsylvania  19104
Hemophilia Ctr of Western PA / Univ of PittsburghPittsburgh, Pennsylvania  15219
Univ of Pittsburgh Med SchoolPittsburgh, Pennsylvania  
Univ of Tennessee / E Tennessee Comprehensive Hemophilia CtrKnoxville, Tennessee  37920
Hermann Hosp / Univ Texas Health Science CtrHouston, Texas  77030
Univ of WashingtonSeattle, Washington  98105
Great Lakes Hemophilia FoundationMilwaukee, Wisconsin  53233
UCLA Med Ctr / PediatricLos Angeles, California  900951752
Univ of South FloridaTampa, Florida  33612
Johns Hopkins HospBaltimore, Maryland  21287
Univ TX Galveston Med BranchGalveston, Texas  77550
Texas Children's Hosp / Baylor UnivHouston, Texas  77030
Univ of Utah School of MedicineSalt Lake City, Utah  84132