Clinical trial NCT00001048: Comparison of Anti HIV Drugs Used Alone or in Combination With Cytosine Arabinoside to Treat Progressive Multifocal Leukoencephalopathy (PML) in HIV-Infected Patients
Official title: A Phase II Multicenter Study Comparing Antiretroviral Therapy Alone to Antiretroviral Therapy Plus Cytosine Arabinoside (Cytarabine; Ara-C) for the Treatment of Progressive Multifocal Leukoencephalopathy (PML) in Human Immunodeficiency Virus (HIV)-Infected Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Leukoencephalopathy, Progressive Multifocal
Keywords: Leukoencephalopathy, Progressive Multifocal
Infusions, Intravenous
Cytarabine
Zalcitabine
Didanosine
Drug Therapy, Combination
Granulocyte Colony-Stimulating Factor
Acquired Immunodeficiency Syndrome
Zidovudine
Injections, Spinal
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Bristol-Myers Squibb
name: Upjohn
First posted: 2001-08-31
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To compare the safety and efficacy of antiretroviral therapy (zidovudine plus either didanosine or dideoxycytidine) versus antiretroviral therapy plus intravenous cytarabine (Ara-C) versus antiretroviral therapy plus intrathecal Ara-C in the maintenance or improvement of neurological function over 6 months in HIV-infected individuals who have developed progressive multifocal leukoencephalopathy (PML). To compare the effect of these three treatment regimens on Karnofsky score and MRI studies.

The effectiveness of Ara-C in the treatment of PML, caused by a human DNA papovavirus (designated JC virus) infection, has not been determined, although the most encouraging results have occurred with intrathecal administration of the drug.

Detailed description: The effectiveness of Ara-C in the treatment of PML, caused by a human DNA papovavirus (designated JC virus) infection, has not been determined, although the most encouraging results have occurred with intrathecal administration of the drug.

Patients are randomized to receive antiretroviral therapy alone (AZT plus ddI or ddC), antiretroviral therapy plus intravenous Ara-C, or antiretroviral therapy plus intrathecal Ara-C. All patients receive 24 weeks of antiretroviral therapy. Beginning at week 2, patients on the intravenous Ara-C arm receive daily infusions of Ara-C over 5 days, with cycles repeating every 21 days. Patients on the intrathecal Ara-C arm receive single administrations of Ara-C at weeks 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24. A brain biopsy confirmation or in situ hybridization will be required within 7 days after study entry. Patients are followed every 4 weeks.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Allowed:

* Local intralesional chemotherapy for mucocutaneous Kaposi's sarcoma.
* Topical antifungals, clotrimazole, ketoconazole, fluconazole, and amphotericin B for treatment of mucosal and esophageal candidiasis.
* Foscarnet for newly developed CMV infection, only after discussion with the protocol chair.
* Prophylactic and maintenance therapy for other opportunistic infections, provided patients are considered clinically stable.
* No more than 1000 mg/day acyclovir for herpes simplex.
* Antibiotics for bacterial infections as clinically indicated.
* Antipyretics, analgesics, and antiemetics.

Concurrent Treatment:

Allowed:

* Local radiation therapy for mucocutaneous Kaposi's sarcoma.

Patients must have:

* HIV infection.
* Confirmed PML.
* No other current active opportunistic infections requiring systemic therapy.
* Life expectancy of at least 3 months.

NOTE:

* A durable power of attorney is recommended where severe neurologic or psychiatric impairment can be foreseen while the patient is on study.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Current active cryptococcal meningitis, cytomegaloviral encephalitis, toxoplasmosis encephalitis, CNS lymphoma, or neurosyphilis.

NOTE:

* Patients on maintenance therapy for cryptococcal meningitis or toxoplasmosis encephalitis that has been stable for 4 months are permitted.
* Conditions that seriously increase risk of a surgical procedure (e.g., coagulopathy, severe thrombocytopenia).
* Any other disease that would interfere with evaluation of the patient.
* Other life-threatening complications likely to cause death in \< 3 months.

Concurrent Medication:

Excluded:

* Ganciclovir.
* Interferon.
* Systemic chemotherapy other than Ara-C (unless specifically allowed).
* Antiretroviral medications other than AZT, ddI, or ddC.

Patients with the following prior conditions are excluded:

History of allergy or intolerance to G-CSF.

Prior Medication:

Excluded:

* Any prior Ara-C.

Excluded within 14 days prior to study:

* Ganciclovir or foscarnet.
* Interferon.
* Antiretroviral medications other than AZT, ddI, or ddC.
* Experimental medications for treatment of PML.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
Study officials:
name: Hall C
role: STUDY_CHAIR
name: Timpone J
role: STUDY_CHAIR
References:
citation: Cytarabine nixed for PML. GMHC Treat Issues. 1996 Nov;10(11):9.
citation: Post MJ, Yiannoutsos C, Simpson D, Booss J, Clifford DB, Cohen B, McArthur JC, Hall CD. Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings useful to patient management and predictive of patient survival? AIDS Clinical Trials Group, 243 Team. AJNR Am J Neuroradiol. 1999 Nov-Dec;20(10):1896-906.
citation: Hall C, Timpone J, Dafni I, Antonijevic Z, Millar L, Booss J, Clifford D, Cohen B, McArthur J, Hollander H. ARA-C treatment of PML in AIDS patients. Conf Retroviruses Opportunistic Infect.1997 Jan 22-26;4th:66 (abstract no 8)PMID: 97926517
citation: Yiannoutsos CT, Major EO, Curfman B, Jensen PN, Gravell M, Hou J, Clifford DB, Hall CD. Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy. Ann Neurol. 1999 Jun;45(6):816-21. doi: 10.1002/1531-8249(199906)45:63.0.co;2-w.
citation: Hall CD, Dafni U, Simpson D, Clifford D, Wetherill PE, Cohen B, McArthur J, Hollander H, Yainnoutsos C, Major E, Millar L, Timpone J. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team. N Engl J Med. 1998 May 7;338(19):1345-51. doi: 10.1056/NEJM199805073381903.
citation: Crit Path AIDS Proj 1994-95 Winer; (No 30): 28-29. A phase II Multicenter Study Comparing Antiretroviral Therapy Alone to Antiretroviral Therapy Plku Cytosine Arabinosine (Cytarabine; Ara-C) for the Treatment of Progressive Multifocal Leukoencephalopathy (PML) in Human Immunodeficiency Virus (HIV)-Infected Subjects. .