Results from the 5-year, phase IV RENEW (Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis) study.

BACKGROUND: Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis (RENEW) was a 5-year, phase IV study in which the safety of Mitoxantrone was monitored in a patient cohort from the United States (US). The objective of the study was to evaluate the long-term safety profile of Mitoxantrone in patients with secondary progressive multiple sclerosis (SPMS), progressive relapsing multiple sclerosis (PRMS), and worsening relapsing-remitting multiple sclerosis (RRMS). METHODS: Overall, 509 patients (395 SPMS, 81 worsening RRMS, 33 PRMS) were enrolled and treated at 46 multiple sclerosis (MS) treatment centers located in the US. Patients received Mitoxantrone in accordance with the package insert every 3 months. During the treatment phase, patients received laboratory workups and cardiac monitoring every 3 months and then annually for a total of 5 years. RESULTS: Five hundred and nine subjects were enrolled in this trial and received at least one infusion of Mitoxantrone. Overall, 172 (33.8%) completed the 5-year trial (i.e., participated for 5 years ± 3 months [treatment + follow-up]); 337 (66.2%) did not complete the 5-year trial. Annual follow-up data were available for 250 of 509 enrolled patients. Left ventricular ejection fraction reduction under 50% was reported in 27 (5.3%) patients during the treatment phase (n = 509) and 14 (5.6%) patients during the annual follow-up phase (n = 250). Signs and symptoms of congestive heart failure were observed in 10 (2.0%) patients (six during treatment phase and four during the annual follow-up phase). Post-hoc analyses of the risk for cardiotoxicity outcomes revealed that cumulative dose exposure is the primary risk factor associated with the risk of cardiac toxicity with Mitoxantrone. Therapy-related leukemia was reported in three (0.6%) patients who received total cumulative Mitoxantrone doses of 73.5 mg/m², 107.3 mg/m², and 97.1 mg/m² respectively. During the treatment phase, persistent amenorrhea developed in 22% (28/128) of women with regular menses and 51% (25/49) of women with irregular menses at baseline. During the annual follow-up phase, persistent amenorrhea developed in 5% (4/73) of women with regular menses at baseline. CONCLUSION: RENEW results are consistent with the known safety profile of Mitoxantrone, and provide additional long-term safety data for Mitoxantrone in MS patients.

Anastrozole vs. clomiphene citrate in infertile women with ovulatory dysfunction: a phase II, randomized, dose-finding study.

OBJECTIVE: To determine an effective multiple-dose regimen of anastrozole compared with clomiphene citrate (CC) to induce follicular growth and ovulation in infertile women with ovulatory dysfunction. DESIGN: Phase II, prospective, randomized, double-blind, multicenter, dose-finding, noninferiority study. SETTING: Outpatient. PATIENT(S): Infertile women (n = 271) with ovulatory dysfunction, aged 18-40 years, with body mass index <37 kg/m(2). INTERVENTION(S): Five days of anastrozole at 1, 5, or 10 mg/d or CC at 50 mg/d. MAIN OUTCOME MEASURE(S): The primary endpoint was the ovulation rate (mid-luteal phase serum P level ≥ 10 ng/mL or clinical pregnancy) in the first treatment cycle (cycle 1). RESULT(S): In cycle 1 the ovulation rates for anastrozole at 1, 5, and 10 mg/d were 30.4% (n = 24), 36.8% (n = 28), and 35.9% (n = 14), respectively, compared with 64.9% (n = 50) for CC at 50 mg/d. In up to three cycles of treatment, cumulative ovulation rates did not differ between groups. No cases of ovarian hyperstimulation syndrome were reported, and both anastrozole and CC were well tolerated. CONCLUSION(S): In terms of ovulation rates, 5-day anastrozole at 1, 5, and 10 mg/d was less effective than CC at 50 mg/d for cycle 1 (noninferiority was not shown).

Anastrozole single-dose protocol in women with oligo- or anovulatory infertility: results of a randomized phase II dose-response study.

OBJECTIVE: To compare the effects of anastrozole and clomiphene citrate (CC) on follicular development and ovulation in infertile women with ovulatory dysfunction. DESIGN: Phase II, prospective, randomized, assessor-blind, multicenter, dose-finding, noninferiority study. SETTING: Outpatient. PATIENT(S): Infertile women with ovulatory dysfunction, aged 18-35 years, and body mass index <35 kg/m(2). INTERVENTION(S): Single-dose anastrozole at 5 mg (n = 39), 10 mg (n = 39), 20 mg (n = 39), or 30 mg (n = 38) or a 5-day course of CC at 50 mg/d (n = 39) as starting doses. MAIN OUTCOME MEASURE(S): The primary endpoint was the ovulation rate in the first treatment cycle (cycle 1). Ovulation was defined as a midluteal phase serum P level ≥ 10 ng/mL or clinical pregnancy. RESULT(S): In cycle 1 the ovulation rates for a single dose of anastrozole at 5, 10, 20, and 30 mg were 46.2%, 41.0%, 23.1%, and 28.9%, respectively, whereas that for CC at 50 mg/d was 61.5%. Among women with fewer than six menses per year, the cumulative ovulation rates over three cycles were comparable in the anastrozole 5 mg (52.4%) and CC 50 mg/d (42.3%) groups. CONCLUSION(S): In terms of ovulation rates in cycle 1, single-dose anastrozole at 5, 10, 20, and 30 mg was not as effective as CC at 50 mg/d for 5 days (noninferiority was not shown).

Effects of growth hormone on abnormal visceral adipose tissue accumulation and dyslipidemia in HIV-infected patients.

BACKGROUND: Some HIV-infected patients develop fat maldistribution with visceral adipose tissue (VAT) accumulation and metabolic abnormalities. No medical treatment is approved by the US Food and Drug Administration to reduce VAT. METHODS: In this double-blind trial, 245 HIV-infected patients with excess VAT were randomized to receive placebo (PL), recombinant human growth hormone (r-hGH) at a dose of 4 mg daily (DD) or 4 mg on alternate days (AD) for 12 weeks. For weeks 12 to 24, DD patients were rerandomized to PL (DD-PL) or AD (DD-AD), AD patients continued on AD (AD-AD), and PL patients were switched to DD (PL-DD). RESULTS: From baseline to week 12, VAT decreased significantly compared with PL in DD (-8.6%, P < 0.001) but not in AD (-4.2%, P = 0.052). Trunk-to-limb fat ratio decreased significantly in both (P < 0.001) compared with PL, as did total cholesterol and non-high-density lipoprotein (HDL) cholesterol (-4.5% and -7.5% in DD, -4.3% and -6.2% in AD). At week 24, all groups displayed significant (P < 0.05) reductions in VAT (-5.3% to -9.5%) and trunk fat (-7.8% to -22.8%). DD-AD and AD-AD also displayed significant (P < 0.05) reductions in non-HDL cholesterol. CONCLUSIONS: These results suggest that r-hGH dosed at 4 mg daily for 12 weeks decreases VAT and cholesterol concentrations in HIV-infected patients with excess VAT. The optimal regimen to sustain these effects awaits determination.