A Phase I/II Study to Evaluate Single Agent and Combination Therapy With Megestrol Acetate and Dronabinol for the Treatment of HIV-Wasting Syndrome

HIV-wasting syndrome, which is characterized by severely debilitating anorexia and weight loss, is of particular concern because it can exacerbate the primary illness and is associated with a poor prognosis. Attempts at maintaining body mass through the use of megestrol acetate and dronabinol, two anti-cachectic drugs, may prolong survival.

Fifty-six patients are randomized to one of four treatment arms, as follows: high-dose megestrol acetate alone; dronabinol alone; high-dose megestrol acetate combined with dronabinol; or low-dose megestrol acetate combined with dronabinol. Treatment continues for 12 weeks. Patients are evaluated for toxicity, preliminary evidence of response (e.g., weight gain), and steady-state pharmacokinetics of drug therapies.

Inclusion criteria

Concurrent Medication:

Allowed:

• Zidovudine (AZT), didanosine (ddI), and dideoxycytidine (ddC). If initiating new antiretroviral therapy, patient must have been on a stable dose for at least 4 weeks prior to study entry.
• Maintenance or suppressive therapy with any of the following, provided patient has been on a stable dose for at least 1 week prior to study entry:
• Ganciclovir or foscarnet for CMV retinitis.
• Fluconazole, amphotericin B, or flucytosine for cryptococcosis.
• Amphotericin B for disseminated histoplasmosis.
• Pyrimethamine, sulfadiazine, dapsone, or clindamycin for toxoplasmosis.
• Amikacin, clarithromycin, clofazimine, ethambutol, ciprofloxacin, or rifampin for disseminated Mycobacterium avium complex.
• Isoniazid, rifampin, ethambutol, or pyrazinamide for M. tuberculosis.
• Any of the following provided patient is on a stable dose for at least 1 week prior to study entry:
• Trimethoprim-sulfamethoxazole, aerosolized pentamidine, or dapsone for Pneumocystis carinii prophylaxis.
• Clotrimazole troches, nystatin suspension, ketoconazole, or fluconazole for oral candidiasis.
• Oral acyclovir for mucocutaneous herpes simplex.
• Narcotic analgesics, tranquilizers, sedative-hypnotics, or anticholinergic agents provided patient is on a stable dose for at least 1 week prior to study entry.

Patients must have:

• HIV infection.
• HIV-wasting syndrome and anorexia.
• Life expectancy of at least 4 months.
• Ability to tolerate oral therapy, feed themselves, and have access to as much food as they desire with no dietary restrictions.

Prior Medication:

Allowed:

• Prior zidovudine (AZT), didanosine (ddI), and dideoxycytidine (ddC).
• Prior maintenance or suppressive therapy for certain opportunistic infections, as follows:
• Ganciclovir or foscarnet for CMV retinitis.
• Fluconazole, amphotericin B, or flucytosine for cryptococcosis.
• Amphotericin B for disseminated histoplasmosis.
• Pyrimethamine, sulfadiazine, dapsone, or clindamycin for toxoplasmosis.
• Amikacin, clarithromycin, clofazimine, ethambutol, ciprofloxacin, or rifampin for disseminated Mycobacterium avium complex.
• Isoniazid, rifampin, ethambutol, or pyrazinamide for M. tuberculosis.

Exclusion criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Major, acute opportunistic infections.
• Active neoplasms other than Kaposi's sarcoma or localized skin carcinoma.
• Diabetes, congestive heart failure, clinical ascites, or uncontrolled hypertension.
• Persistent grade 3/4 diarrhea.
• Impaired oral intake, such as occurs with Candida esophagitis or severe mouth ulcers.
• Clinically significant cardiac arrhythmias.
• Requirement for anticonvulsants for seizure disorder.

Concurrent Medication:

Excluded:

• Marijuana use.
• Anabolic steroids.
• Anticonvulsants for seizure disorders.
• Alcohol or barbiturates.

Patients with the following prior conditions are excluded:

• Diagnosis of a major, acute opportunistic infection within 2 months prior to study entry.
• Hospitalization within 2 weeks prior to study entry.
• History of hypersensitivity reactions to megestrol acetate, dronabinol, or sesame oil (a component of the dronabinol capsules).
• History of thromboembolic events.
• History of psychiatric disorder other than depression.

Prior Medication:

Excluded:

• Prior dronabinol.
• Megestrol acetate within 2 months prior to study entry.
• Marijuana within 1 month prior to study entry.
• Anabolic steroids within 3 months prior to study entry.

Current drug or alcohol abuse (patients with a history of occasional marijuana use are eligible provided they have abstained from its use for 1 month prior to study entry and agree to refrain from marijuana use for the study period).