Clinical trial NCT00000768: A Randomized Comparative Pharmacokinetic Study of Oral Ganciclovir After Treatment With Intravenous Ganciclovir for Cytomegalovirus Gastrointestinal Disease in AIDS Patients
Official title: A Randomized Comparative Pharmacokinetic Study of Oral Ganciclovir After Treatment With Intravenous Ganciclovir for Cytomegalovirus Gastrointestinal Disease in AIDS Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Colitis
HIV Infections
Keywords: Intestinal Absorption
Ganciclovir
Drug Therapy, Combination
Cytomegalovirus Infections
Colitis
Administration, Oral
Acquired Immunodeficiency Syndrome
Biological Availability
Glutamic Acid
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Hoffmann-La Roche
First posted: 2001-08-31
Enrollment: 24
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: To determine the oral bioavailability of three dose levels of oral ganciclovir given with and without glutamic acid hydrochloride in patients with cytomegalovirus (CMV) GI disease, and to compare the bioavailability of these regimens to that of standard intravenous (IV) ganciclovir.

Long-term ganciclovir maintenance therapy has been recommended for CMV colitis or esophagitis following induction treatment. Oral ganciclovir is a likely candidate for maintenance because of its possible therapeutic value and ease of administration, but an optimum dose has not been determined. Since oral ganciclovir has a low bioavailability and is more soluble in an acid pH environment, the addition of glutamic acid hydrochloride may enhance gastrointestinal absorption of this drug.

Detailed description: Long-term ganciclovir maintenance therapy has been recommended for CMV colitis or esophagitis following induction treatment. Oral ganciclovir is a likely candidate for maintenance because of its possible therapeutic value and ease of administration, but an optimum dose has not been determined. Since oral ganciclovir has a low bioavailability and is more soluble in an acid pH environment, the addition of glutamic acid hydrochloride may enhance gastrointestinal absorption of this drug.

All patients receive an induction regimen of IV ganciclovir administered twice daily for 21 to 42 (Per Amendment 3/4/95) days. A permanent venous catheter is implanted for the induction therapy. If clinically improved following induction, patients are then randomized to receive one of three doses of oral ganciclovir, given first without and then with oral glutamic acid hydrochloride, every 8 hours until they reach a steady state. PER AMENDMENT 3/14/95: After subjects have reached steady state with oral ganciclovir and glutamic acid hydrochloride then PK samples will be taken. Subjects will continue the dosing regimen they were assigned to (glutamic acid hydrochloride will be added if it resulted in at least 33% increased bioavailability) for up to 12 months or until relapse of CMV GI disease is documented. Subjects will be followed at monthly intervals for safety evaluation and for evidence of CMV GI relapse. Subjects who have clinical symptoms of relapse will undergo repeat endoscopy or colonoscopy to document the relapse.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Recommended:

* PCP prophylaxis.

Allowed:

* Antiretroviral therapy during induction and pharmacokinetic part of study, provided patient remains on the same antiretroviral therapy for the duration of the study.
* Chemotherapy for Kaposi's sarcoma, provided patient is hematologically stable for at least 30 days prior to study entry.
* Recombinant human erythropoietin.
* GM-CSF and G-CSF.
* Other medications necessary for patient's welfare, at the physician's discretion.

Patients must have:

* HIV infection.
* Biopsy-proven cytomegalovirus (CMV) colitis.
* Life expectancy of at least 3 months.
* No active AIDS-defining opportunistic infection requiring therapy that is known to cause nephrotoxicity or myelosuppression.

NOTE:

* Kaposi's sarcoma is permitted if patients are hematologically stable for at least 30 days prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Other etiologies for diarrhea identified at study entry.

PER AMENDMENT 3/14/95:

* For subjects who have diarrhea - no other etiologies for diarrhea identified within 6 weeks of enrollment.
* Known hypersensitivity to study drugs.
* CMV retinitis.

Concurrent Medication:

Excluded:

* Acyclovir or probenecid (PER AMENDMENT 3/14/95).
* Immunomodulators.
* Biologic response modifiers (other than GM-CSF or G-CSF).
* Investigational agents, with the exception of treatment IND drugs.
* Antacids.
* H2 blockers.
* Proton pump inhibitors.
* Foscarnet during induction and pharmacokinetic part of study.
* Intravenous CMV retinitis maintenance therapy (including ganciclovir) during pharmacokinetic part of study.
* Nephrotoxic agents.

Prior Medication:

Excluded within 14 days prior to study entry:

* Immunomodulators.
* Biologic response modifiers (other than GM-CSF or G-CSF).
* Investigational agents, with the exception of treatment IND drugs.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
Study officials:
name: Jacobson M
role: STUDY_CHAIR
name: Dieterich D
role: STUDY_CHAIR
name: Kotler D
role: STUDY_CHAIR
name: Laine L
role: STUDY_CHAIR
name: Kumar P
role: STUDY_CHAIR
References:
citation: Dieterich DT, Kotler DP, Busch DF, Crumpacker C, Du Mond C, Dearmand B, Buhles W. Ganciclovir treatment of cytomegalovirus colitis in AIDS: a randomized, double-blind, placebo-controlled multicenter study. J Infect Dis. 1993 Feb;167(2):278-82. doi: 10.1093/infdis/167.2.278.