Purpose:
To determine the pharmacokinetics profile of single doses of nitazoxanide (NTZ) in patients
with AIDS-related cryptosporidial diarrhea. To determine steady state concentrations of NTZ
following repeated dosing. To assess the safety and efficacy of 4 dose levels of NTZ in
these patients.
Cryptosporidial enterocolitis in AIDS patients is frequently chronic and severe,
contributing substantially to morbidity, mortality, and health care costs in this
population. NTZ exhibits antimicrobial activity that may extend to Cryptosporidial
infection.
Study summary:
Cryptosporidial enterocolitis in AIDS patients is frequently chronic and severe,
contributing substantially to morbidity, mortality, and health care costs in this
population. NTZ exhibits antimicrobial activity that may extend to Cryptosporidial
infection.
Patients are enrolled in groups of 7. Group A receives the lowest dose of NTZ. Groups B - D
receive sequentially higher doses. Patients in Groups B - D do not begin therapy until all
patients have been enrolled at the preceding dose. For determination of single-dose
pharmacokinetics, patients receive a single dose of NTZ on Day 1 and blood samples are
obtained over the next 24 hours. Immediately following the 24-hour blood sample collection,
patients begin the treatment phase during which they take NTZ for an additional 13 days.
Blood samples are obtained again on Day 14 to determine full plasma concentration-time
profiles over the dosing interval. At the end of treatment, responders discontinue treatment
and nonresponders continue NTZ treatment for an additional 14 days on the same dose.
Patients who still fail to respond are provided with an additional month of NTZ. Patients
have scheduled visits for clinical and parasitologic efficacy assessments and safety
laboratory tests.
Criteria:
Inclusion Criteria
Patients must have:
- AIDS diagnosis according to CDC criteria.
- CD4 count less than or equal to 200 cells/mm3 or CD4 count greater than or equal to
200 cells/mm3 and documented cryptosporidiosis for a minimum of 4 weeks.
- Cryptosporidial diarrhea as defined by:
- (1) presence of Cryptosporidium oocytes in a stool specimen within 14 days of
enrollment; and (2) chronic diarrhea (i.e., an average of at least 4 bowel movements
per day for a minimum of 2 weeks).
- Life expectancy of at least 1 month.
- Ability to tolerate food by mouth.
Prior Medication:
Required:
- Any anti-diarrheal or anti-emetic medication for which the dosage regimen has been
stable for at least 1 week prior to enrollment.
- Any antiretroviral medications (e.g., zidovudine, ddI, ddC) for which the dosage
regimen has been stable for at least 3 weeks prior to enrollment.
Allowed:
Medication for prophylaxis or maintenance therapy of opportunistic infection, stable for
at least 2 weeks prior to enrollment.
Exclusion Criteria
Co-existing Condition:
Patients with the following symptoms or conditions are excluded:
Grade 4 (hematologic) or Grade 3 (for all others) toxicity. (Patients with Grade 3
toxicity for hepatic parameters may be enrolled if, in the investigator's judgment, the
abnormalities are due to biliary cryptosporidiosis.)
Patients with the following prior conditions are excluded:
- Presence of Salmonella, Shigella, Campylobacter, Yersinia, Giardia lamblia, Entamoeba
histolytica, Microsporidia, Isospora, Cyclospora, or Clostridium difficile toxin in
stool (based on assessment within 14 days prior to enrollment by stool ova and
parasite examination, culture, and C. difficile assay).
- History of intestinal Mycobacterium avium intracellular infection or intestinal
Kaposi's sarcoma.
- History of Cytomegalovirus colitis, unless 28 days of therapy with ganciclovir or
foscarnet completed subsequent to diagnosis.
Prior Medication:
Excluded:
- Investigational drug therapy within 14 days of enrollment, unless available under an
FDA-authorized expanded access program.
- Any drug or therapy with possible anticryptosporidial activity (e.g., paromomycin,
spiramycin, azithromycin, clarithromycin, hyperimmune bovine colostrum) within 14
days of enrollment.