Laurie Smaldone

A Controlled Trial Comparing Continued Zidovudine with Didanosine in Human Immunodeficiency Virus Infection

BACKGROUND Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine. METHODS This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with less than or equal to 300 CD4 cells per cubic milliliter, or asymptomatic HIV infection with less than or equal to 200 CD4 cells per cubic milliliter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine. RESULTS There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P less than 0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group. CONCLUSIONS Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease.

Carboplatin: current status and future prospects

During the past decade more than a dozen derivatives of cisplatin have reached the stage of clinical development. Carboplatin (cis-diammine-cyclobutane, dicarboxylato platinum II, CBDCA, JM-8, Paraplatin 8) is the first of these compounds to become widely available to the oncologist. Clinical trials of carboplatin began in 1981, and a great deal of information has been gathered since. This paper proposes to update our earlier clinical review (16) encompassing the existing literature data base up to November 1987.

Megestrol acetate: clinical experience.

The use of megestrol acetate in treatment of malignancy (endometrial carcinoma, ovarian cancer, prostate cancer, breast cancer, renal cell carcinoma, malignant melanoma), endometrial hyperplasia, benign prostatic hypertrophy, contraception, anorexia, cachexia and weight loss is reviewed, concluding with a toxicity profile. Megestrol acetate was introduced in 1971 for treatment of endometrial carcinoma. Megestrol acetate is probably effective in proportion to the number of cytoplasmic progesterone receptors, but it has not been tested in a Phase III trial. For ovarian cancer it has been reported to be effective in 1 trail at doses of 800 mg/day. Prostate cancer, although difficult to assess, responds to megestrol acetate at doses of 120 mg/day because of its suppression of gonadotropins, its inhibition of 5alpha-reductase and its binding to the dihydrotestosterone receptor. Megestrol acetate permits a lower dose of diethylstilbestrol, and thus lower toxicity. There is apparently a dose-response between megestrol acetate and breast cancer, along with a response dependent on the number and type of estrogen and progestin receptors. Responses are better in postmenopausal women, and additive with other agents such as tamoxifen and mitomycin C. The medium duration of effect is 6-8 months. It has no effect on renal cancer or malignant melanoma. Megestrol acetate can be considered as an effective medical alternative to surgery for endometrial hyperplasia or benign prostatic hypertrophy. As a contraceptive in inhibits sperm transport rather than ovulation, but also causes irregular bleeding. Megestrol acetate has few side effects, and has the advantage of stimulating appetite and weight gain, a benefit in cancer patients.

Didanosine Compared with Continued Zidovudine Therapy for HIV-Infected Patients with 200 to 500 CD4 Cells/mm3: A Double-Blind, Randomized, Controlled Trial

Zidovudine (3-azido-3-deoxythymidine) has been shown in placebo-controlled studies [1, 2] to prolong survival in patients with the acquired immunodeficiency syndrome (AIDS), to delay the development of AIDS in those with AIDS-related complex, and to delay the development of AIDS and AIDS-related complex in patients with asymptomatic human immunodeficiency virus (HIV) infection. The duration of the clinical benefit afforded by zidovudine monotherapy, however, appears to be limited [3-6]. The underlying mechanism or mechanisms responsible for disease progression during zidovudine therapy must still be definitively established. However, current evidence suggests that the development of viral resistance to zidovudine is at least partly responsible for the short duration of benefit [7, 8]. Didanosine (2,3-dideoxyinosine) is a newer nucleoside analog that has been shown to be effective in vitro against HIV [9]. Didanosine has in vitro activity against viral isolates that have high-level resistance to zidovudine [10]. Early clinical trials showed that didanosine can have a persistent beneficial effect on surrogate markers of HIV infection, such as CD4 counts, p24 antigen levels, and constitutional symptoms [11-14]. The investigators who did these studies found that peripheral neuropathy and pancreatitis were the dose-limiting toxicities of didanosine. More recently, controlled studies have shown that a switch to didanosine can improve clinical outcome in persons with advanced HIV disease who have received zidovudine [15, 16]. More specifically, Kahn and colleagues [15] showed such a benefit in patients with AIDS or AIDS-related complex who were clinically stable while receiving zidovudine and who had CD4 counts of 300 cells/mm3 or less and in asymptomatic HIV-infected patients with CD4 counts of 200 cells/mm3 or less. Spruance and coworkers [16] showed a similar benefit in patients with CD4 counts of 300 cells/mm3 or less and signs of clinical deterioration while receiving zidovudine therapy. No clinical data are available on the role of didanosine in stable patients in earlier stages of HIV disease who have received zidovudine. We therefore specifically compared the safety and efficacy of didanosine with that of continued zidovudine therapy in clinically stable HIV-infected persons who had CD4 counts between 200 and 500 cells/mm3 and had received zidovudine for at least 6 months. We hypothesized that a change to a second effective antiretroviral agent before the anticipated development of high-level resistance to zidovudine would prevent resistance and consequently delay the progression of HIV disease. Methods Study Design Randomization was stratified by the study center and by the CD4 cell count at study enrollment (more than or less than 300 cells/mm3). Successfully screened patients were randomly assigned using computer-generated random numbers. Randomization was done at a central location to ensure that patients, research personnel, and pharmacists remained blinded to the treatment allocation. All study participants provided informed consent. The study protocol and informed consent were approved by the review boards of the participating institutions and by the Canadian HIV Trials Network (CTN), with which our study is registered as protocol CTN-002. Patients Eligible study participants were male and nonpregnant female patients 12 years of age or older. Other entry criteria were the following: 1) HIV infection documented by enzyme-linked immunosorbent assay; 2) two sequential prerandomization CD4 counts between 200 and 500 cells/mm3 obtained at least 72 hours apart within 30 days of randomization, with the most recent measurement done within 14 days of randomization; 3) zidovudine therapy received for at least 6 months before randomization at a dose of at least 500 mg/d for the month immediately preceding study entry; 4) zidovudine therapy at 500 mg/d or greater for at least 21 of the previous 26 weeks; 5) a Karnofsky performance status of greater than 60 at study entry; 6) a hemoglobin level greater than 85 g/L or a hematocrit greater than 0.25 (in the absence of blood transfusion in the preceding 2 weeks); 7) a neutrophil count greater than 0.75 109/L; 8) a platelet count greater than 50 109/L; 9) serum aminotransferase and alkaline phosphatase levels greater than five times the upper limit of normal; 10) a serum creatinine level greater than 1.5 times the upper limit of normal; 11) a serum uric acid level less than 530 mol/L; and 12) a serum amylase level less than 2.1 times the upper limit of normal. The following are the normal values for chemical variables: aspartate aminotransferase, as high as 0.67 kat/L; alkaline phosphatase, 0.58 to 1.75 kat/L; creatinine, 40 to 120 mol/L; and amylase, 0.50 to 1.83 kat/L. Study participants were required to take adequate birth control measures during the study. The following were the exclusion criteria: 1) the presence of an uncontrolled AIDS-defining illness; 2) known or suspected pulmonary Kaposi sarcoma or Kaposi sarcoma requiring systemic cytotoxic chemotherapy; 3) grade II or greater dementia; 4) active substance abuse; 5) antiretroviral therapy other than zidovudine; 6) any use of biological-response modifiers or corticosteroids within 30 days of entry or therapy with ribavirin within 90 days of entry; 7) previous participation in studies involving didanosine or zalcitabine; 8) grade II or greater neurologic, allergic, or renal toxicities; 9) any history of pancreatitis, intractable diarrhea, or malabsorption; 10) unexplained seizures within the previous 6 months or need for anticonvulsant agents; 11] treatment with neurotoxic drugs within 30 days of entry; and 12) past or current heart disease or requirement for cardiac medication. All study participants were encouraged to use prophylaxis for Pneumocystis carinii infection according to contemporary guidelines [17]. The use of megestrol acetate, foscarnet, aspirin, acetaminophen, nonsteroidal anti-inflammatory agents, oral acidifying agents, and oral acyclovir was discouraged. Treatment of opportunistic infections was permitted. In patients developing serious symptoms or laboratory abnormalities, study medications were withheld until the symptoms or laboratory abnormalities resolved; at this point, patients were encouraged to resume the study medication, according to a prespecified dose-reduction scheme. Treatment Regimens Zidovudine (Retrovir, Burroughs-Wellcome, Research Triangle Park, North Carolina) was provided in 100-mg capsules to be taken at a dosage of 600 mg/d divided into at least three daily doses. Didanosine (Videx, Bristol-Myers Squibb, Princeton, New Jersey) was provided in sachets containing 5.2 g of citrate-phosphate buffer and sucrose adjusted to yield a final net weight of 20 g. The contents of one sachet were to be dissolved in water and swallowed. Didanosine dosage was adjusted for weight: Patients weighing at least 60 kg received 500 mg/d in two divided doses; patients weighing less than 60 kg received 334 mg/d in two divided doses. The didanosine formulation was changed in October 1991 from 500- and 334-mg/d sachet formulations to 400- and 200-mg/d tablet formulations. Study participants were instructed to chew the didanosine tablets thoroughly either together or in rapid succession and then to rinse with approximately 120 mL of room-temperature drinking water, which was also to be swallowed. Alternatively, the two tablets were to be crushed and thoroughly dispersed in at least 120 mL of drinking water; this solution was to be drunk immediately, followed by approximately 120 mL of drinking water. Study participants were instructed to always take didanosine on an empty stomach, at least 2 hours after and 1 hour before meals. To maintain the double-blind nature of the protocol, patients assigned to receive didanosine were given identical zidovudine placebo, and those assigned to receive zidovudine were given identical didanosine placebo. Follow-up After completion of the baseline evaluation, patients were seen at biweekly intervals for the first 2 months and monthly thereafter. A safety profile, including a symptom-targeted questionnaire, hematologic assessment, and chemistry panel were done at each visit. The CD4 count and viral resistance studies were done at baseline; at weeks 2, 8, and 12; and every 3 months thereafter. Formal follow-up of this cohort, as per the study protocol, was completed on 12 October 1992. Long-term, off-protocol, follow-up information on survival, AIDS-defining illnesses, and CD4 lymphocyte counts was compiled on one occasion using standardized data collection forms in December 1993. This allowed us to collect additional follow-up information on all patients after study completion and information on the complete study period for patients who dropped out of the study. Study End Points The primary clinical end point was the occurrence of a new, previously undiagnosed AIDS-defining event (according to the revised 1987 criteria of the Centers for Disease Control and Prevention) or death [18]. Clinical end points were reviewed by study monitors at each clinical site and were confirmed in a blinded manner by the clinical end points committee. Didanosine was licensed by the Food and Drug Administration in the United States and by the Health Protection Branch in North America in the fall of 1991. At that time, didanosine became the standard therapy in Canada for persons with zidovudine intolerance or disease progression despite zidovudine therapy. Thus, in late 1991, while the study remained blinded and before any data were analyzed, a 33% decline in CD4 counts from baseline was added as a primary study end point to maintain consistency with prevailing clinical practice. Sensitivity Testing Samples for testing sensitivity to the study drugs were obtained from 102 of 120 patients (85%) enrolled at five clinical sites who were preselected on the basis of logistic issues. For

Double-blind, randomized crossover study of metoclopramide and batanopride for prevention of cisplatin-induced emesis

SummaryWe conducted a double-blind, randomized crossover study to compare the toxicity and antiemetic efficacy of the 5-hydroxytryptamine3 receptor antagonist batanopride with that of metoclopramide in 21 chemotherapy-naive patients receiving at least 70 mg/m2 cisplatin. The study was terminated when hypotension was observed following the infusion of batanopride at other institutions testing similar drug schedules. Although we observed no hypotension following treatment with batanopride in this trial, we did note asymptomatic prolongation of the corrected QT interval (QTc), PR interval, and QRS complex on the EKG in the batanopride arm. Of 15 evaluable patients, 8 experienced ≦2 episodes of emesis within 24 h of the first batanopride infusion, whereas 9/15 subjects experienced ≦2 emetic episodes following the administration of metoclopramide. Overall, the evidence suggests that this dosing schedule for batanopride may be too toxic for clinical used.