Estimated distribution of malaria cases among children in sub-Saharan Africa by specified age categories using data from the Global Burden of Diseases 2019.

BACKGROUND: Children in sub-Saharan Africa (SSA) remain the most vulnerable to malaria and malaria mortality. This study estimated the disease burden and distribution of Plasmodium falciparum malaria among children with age categories (0 to < 2 years, 2 to < 6 years, 6 to < 12 years, ≥ 12 years) in SSA. METHODS: Data on the number of cases and incidence rates of P. falciparum malaria by age group from the Institute of Health Metrics and Evaluation (GBD 2019) for 11 countries in SSA was employed in this study. The best-fitting distribution of P. falciparum malaria cases by prespecified age categories was derived using a combination of a Log-normal and Weibull distribution. RESULTS: Plasmodium falciparum malaria was 15.4% for ages 0 to < 2 years, 30.5% for 2 to < 6 years, 17.6% for 6 to < 12 years, and 36.5% for ≥ 12 years based on data from countries in SSA. The results have important implications for the current drive by the FDA and EMA to ensure the representativeness of real-world populations in clinical trials evaluating the safety and efficacy of medication exposure. CONCLUSIONS: The theoretical distributions of P. falciparum malaria will help guide researchers in ensuring that children are appropriately represented in clinical trials and other interventions aiming to address the current burden of malaria in SSA.

Prescription patterns and compliance with World Health Organization recommendations for the management of uncomplicated and severe malaria: A prospective, real-world study in sub-Saharan Africa.

BACKGROUND: This study aimed to evaluate the gap between guidelines and local clinical practice for diagnosis and treatment of uncomplicated and severe malaria, the patient characteristics, diagnostic approach, treatment, and compliance to standard guideline recommendations. METHODS: This was a multicentre, observational study conducted between October 2020 and March 2021 in which patients of all ages with symptoms suggestive of malaria and who visited a healthcare facility were prospectively enrolled in six countries in sub-Saharan Africa (The Democratic Republic of the Congo, Mozambique, Nigeria, Rwanda, The United Republic of Tanzania, and Zambia). RESULTS: Of 1001 enrolled patients, 735 (73.4%) patients had confirmed malaria (based on overall judgment by investigator) at baseline (uncomplicated malaria: 598 [81.4%] and severe malaria: 137 [18.6%]). Of the confirmed malaria patients, 533 (72.5%) were administered a malaria rapid diagnostic test. The median age of patients was 11 years (range: 2 weeks-91 years) with more patients coming from rural (44.9%) than urban (30.6%) or suburban areas (24.5%). At the community level, 57.8% of patients sought advice or received treatment for malaria and 56.9% of patients took one or more drugs for their illness before coming to the study site. In terms of early access to care, 44.1% of patients came to the study site for initial visit ≥ 48 h after symptom onset. In patients with uncomplicated malaria, the most prescribed treatments were artemisinin-based combination therapy (ACT; n = 564 [94.3%]), primarily using artemether-lumefantrine (82.3%), in line with the World Health Organization (WHO) treatment guidelines. In addition, these patients received antipyretics (85.6%) and antibiotics (42.0%). However, in those with severe malaria, only 66 (48.2%) patients received parenteral treatment followed by oral ACT as per WHO guidelines, whereas 62 (45.3%) received parenteral treatment only. After receiving ambulatory care, 88.6% of patients with uncomplicated malaria were discharged and 83.2% of patients with severe malaria were discharged after hospitalization. One patient with uncomplicated malaria having multiple co-morbidities and three patients with severe malaria died. CONCLUSIONS: The findings of this study suggest that the prescribed treatment in most patients with uncomplicated malaria, but not of those with severe malaria, was in alignment with the WHO recommended guidelines.

Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial.

BACKGROUND: Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria. METHODS: This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (>1000 and <150 000 parasites per µL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and <12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to <6 years and 6 to <12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020-003284-25) and ClinicalTrials.gov (NCT03167242). FINDINGS: Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81-98] with 1 day, 47 of 48 [98%, 89-100] with 2 days, and 42 of 43 [98%, 88-100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83-99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93-100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92-100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86-100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83-99] vs 21 of 22 [96%, 77-100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study. INTERPRETATION: Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633). FUNDING: Novartis and Medicines for Malaria Venture.

Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria.

BACKGROUND: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). METHODS: This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. RESULTS: All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. CONCLUSIONS: Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT03334747).

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa.

BACKGROUND: The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether-lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa. METHODS: This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether-lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial. RESULTS: Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether-lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether-lumefantrine. Cipargamin was well tolerated with no safety concerns. CONCLUSIONS: This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin. Trial registration ClinicalTrials.gov number: NCT03334747 (7 Nov 2017), other study ID CKAE609A2202.

A proof-of-concept-to-confirmatory multiple adaptation design in the development of an anti-viral treatment.

In the clinical development of some new infectious disease drugs, early clinical pharmacology trials may predict with high confidence that the efficacious doses are well below the range of the safety margin. In this case, a dose-ranging study may be unnecessary after a proof-of-concept (PoC) study testing the highest dose. A multi-stage adaptive design spanning both PoC and confirmatory stages is proposed in this context. The design incorporates two interim analyses allowing strategies for stopping, continuing, or expanding the study. A conditional power threshold for a binary endpoint is proposed to assess futility. Additional components of early efficacy and sample size adjustment are also included to enhance the design's flexibility and robustness. Design operating characteristics are evaluated by numerical calculation. We show that the proposed streamlined trial design has the same statistical rigor as a conventional phase 3 clinical trial with adequate power and a properly controlled type 1 error rate. Additional adaptive design options are also investigated and discussed.

Effect of zoledronic acid on serum calcium in Paget's disease patients after educational strategies to improve calcium and vitamin D supplementation.

OBJECTIVE: Bisphosphonates are the most effective therapeutic agents in patients with Paget's disease of bone. As a result of their inhibition of osteoclastic activity, hypocalcemia of variable frequency and severity following intravenous bisphosphonate therapy has been reported. The present study assessed the effect of physician and patient education on adequate supplementation of calcium and vitamin D to reduce the potential risk of developing hypocalcemia following infusion of 5 mg zoledronic acid. METHODS: This was an open-label, multicenter, controlled registry trial in which patients with Paget's disease were treated with a single intravenous infusion of zoledronic acid. Physicians were provided with educational materials focusing on optimization of calcium and vitamin D supplementation following zoledronic infusion that they used to educate their patients. The primary safety variable was the percentage of patients with serum calcium level <2.07mmol/l 9-11 days after zoledronic acid infusion. RESULTS: A total of 75 patients were evaluable in the post dose hypocalcemia safety analysis. Of these, only 1 patient had treatment-emergent hypocalcemia, with a serum calcium level of 1.92 mmol/l 4 days following therapy. Hypocalcemia-related symptoms were not reported in this patient and the serum calcium returned to normal range at 2.17 mmol/l within 1 week on oral calcium supplementation. CONCLUSIONS: These results suggest that, with optimization of calcium and vitamin D supplementation by physician and patient education, hypocalcemia is an infrequent occurrence following zoledronic acid infusion.

Subgroup variations in bone mineral density response to zoledronic acid after hip fracture.

Minimizing post-fracture bone loss is an important aspect of recovery from hip fracture, and determination of factors that affect bone mineral density (BMD) response to treatment after hip fracture may assist in the development of targeted therapeutic interventions. A post hoc analysis of the HORIZON Recurrent Fracture Trial was done to determine the effect of zoledronic acid (ZOL) on total hip (TH) and femoral neck (FN) BMD in subgroups with low-trauma hip fracture. A total of 2127 patients were randomized (1:1) to yearly infusions of ZOL 5 mg (n = 1065) or placebo (n = 1062) within 90 days of operation for low-trauma hip fracture. The 1486 patients with a baseline and at least one post-baseline BMD assessment at TH or FN (ZOL = 745, placebo = 741) were included in the analyses. Percentage change from baseline in TH and FN BMD was assessed at months 12 and 24 and compared across subgroups of hip fracture patients. Percentage change from baseline in TH and FN BMD at months 12 and 24 was greater (p < 0.05) in ZOL-treated patients compared with placebo in most subgroups. Treatment-by-subgroup interactions (p < 0.05) indicated that a greater effect on BMD was observed for TH BMD at month 12 in females, in patients in the lower tertile body mass index at baseline (≤22.6 kg/m(2) ), and in patients with baseline FN BMD T-score of ≤ -2.5; for FN BMD in patients who received ZOL for >6 weeks post-surgery; and for TH and FN BMD in patients with a history of one or more prior fractures. All interactions were limited to the first 12 months after treatment with none observed for the 24-month comparisons. (Clinical trial registration number NCT00046254.)

Effect on bone turnover markers of once-yearly intravenous infusion of zoledronic acid versus daily oral risedronate in patients treated with glucocorticoids.

OBJECTIVE: Long-term glucocorticoid use is accompanied by rapid bone loss; however, early treatment with bisphosphonates prevents bone loss and reduces fracture risk. The aim of this study was to examine the effects of two bisphosphonates, i.v. zoledronic acid (ZOL) versus oral risedronate (RIS), on bone turnover markers (BTMs) in subjects with glucocorticoid-induced osteoporosis (GIO). METHODS: Patients were randomly stratified according to the duration of pre-study glucocorticoid therapy [prevention subpopulation (ZOL, n = 144; RIS, n = 144) ≤3 months, treatment subpopulation (ZOL, n = 272; RIS, n = 273) >3 months]. Changes in ß-C-terminal telopeptides of type 1 collagen (ß-CTx), N-terminal telopeptide of type I collagen (NTx), procollagen type 1 N-terminal propeptide (P1NP) and bone-specific alkaline phosphatase (BSAP) from baseline were measured on day 10 and months 3, 6 and 12. RESULTS: At most time points, there were significantly greater reductions (P < 0.05) in the concentrations of serum ß-CTx, P1NP and BSAP and urine NTx in subjects on ZOL compared with RIS in both males and females of the treatment and prevention subpopulations. In pre- and post-menopausal women, there were significantly greater reductions in the concentrations of BTMs with ZOL compared with RIS. At 12 months, ZOL had significantly greater reductions compared with RIS (P < 0.05) for ß-CTx, P1NP, BSAP and NTx levels, independent of glucocorticoid dose. CONCLUSIONS: Once-yearly i.v. infusion of ZOL 5 mg was well tolerated in different subgroups of GIO patients. ZOL was non-inferior to RIS and even superior to RIS in the response of BTMs in GIO patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00100620.

Re-treatment of relapsed Paget's disease of bone with zoledronic acid: results from an open-label study.

Six patients from the phase 3 trials of zoledronic acid in Paget's disease, who had received zoledronic acid initially and had subsequently relapsed, were entered into an open re-treatment study. Following re-treatment, each patient reached similar absolute nadirs of serum alkaline phosphatase to those recorded after their first dose. No significant adverse events were reported. It is concluded that, while re-treatment of Paget's disease with zoledronic acid is rarely needed, it is safe and effective, with no evidence of treatment resistance based on this small cohort.

Fracture risk and zoledronic acid therapy in men with osteoporosis.

BACKGROUND: Fractures in men are a major health issue, and data on the antifracture efficacy of therapies for osteoporosis in men are limited. We studied the effect of zoledronic acid on fracture risk among men with osteoporosis. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1199 men with primary or hypogonadism-associated osteoporosis who were 50 to 85 years of age to receive an intravenous infusion of zoledronic acid (5 mg) or placebo at baseline and at 12 months. Participants received daily calcium and vitamin D supplementation. The primary end point was the proportion of participants with one or more new morphometric vertebral fractures over a period of 24 months. RESULTS: The rate of any new morphometric vertebral fracture was 1.6% in the zoledronic acid group and 4.9% in the placebo group over the 24-month period, representing a 67% risk reduction with zoledronic acid (relative risk, 0.33; 95% confidence interval, 0.16 to 0.70; P=0.002). As compared with men who received placebo, men who received zoledronic acid had fewer moderate-to-severe vertebral fractures (P=0.03) and less height loss (P=0.002). Fewer participants who received zoledronic acid had clinical vertebral or nonvertebral fractures, although this difference did not reach significance because of the small number of fractures. Bone mineral density was higher and bone-turnover markers were lower in the men who received zoledronic acid (P<0.05 for both comparisons). Results were similar in men with low serum levels of total testosterone. The zoledronic acid and placebo groups did not differ significantly with respect to the incidence of death (2.6% and 2.9%, respectively) or serious adverse events (25.3% and 25.2%). CONCLUSIONS: Zoledronic acid treatment was associated with a significantly reduced risk of vertebral fracture among men with osteoporosis. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00439647.).

Time to onset of antifracture efficacy and year-by-year persistence of effect of zoledronic acid in women with osteoporosis.

Oral bisphosphonates reduce fracture risk in osteoporotic patients but are often associated with poor compliance, which may impair their antifracture effects. This post hoc analysis assessed the time to onset and persistence of the antifracture effect of zoledronic acid, a once-yearly bisphosphonate infusion, in women with osteoporosis. Data from 9355 women who were randomized in two placebo-controlled pivotal trials were included. Endpoints included reduction in the rate of any clinical fracture at 6, 12, 18, 24, and 36 months in the zoledronic acid group compared with placebo, and the year-by-year incidence of all clinical fractures over 3 years. Cox proportional hazards regression was used to determine the timing of onset of antifracture efficacy. A generalized estimating equation model was used to assess fracture reduction for the 3 consecutive years of treatment, thereby evaluating persistence of effect. Safety results from women in the two studies were collated. Zoledronic acid reduced the risk of all clinical fractures at 12 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] 0.61-0.92, p = 0.0050) with significant reductions maintained at all subsequent time points. Year-by-year analysis showed that zoledronic acid reduced the risk for all clinical fractures compared with the placebo group in each of the 3 years (year 1: odds ratio [OR] = 0.74, 95% CI 0.60-0.91, p = 0.0044; year 2: OR = 0.53, 95% CI 0.42-0.66, p < 0.0001; year 3: OR = 0.61, 95% CI 0.48-0.77, p < 0.0001). This antifracture effect was persistent over 3 years, with the reductions in years 2 and 3 slightly larger than in year 1 (p = 0.097). This analysis shows that zoledronic acid offered significant protection from clinical fractures as early as 12 months. When administered annually, its beneficial effects persisted for at least 3 years.

Bisphosphonates and glucocorticoid osteoporosis in men: results of a randomized controlled trial comparing zoledronic acid with risedronate.

BACKGROUND: We studied 265 men (mean age 56.4 years; range 18-83 years), among patients enrolled in two arms of a double-blind, 1-year study comparing the effects of zoledronic acid (ZOL) with risedronate (RIS) in patients either commencing (prednisolone 7.5 mg/day or equivalent) (prevention arm, n=88) or continuing glucocorticoid therapy (treatment arm, n=177). METHODS: Patients received either a single ZOL 5 mg infusion or RIS 5 mg oral daily at randomization, along with calcium (1000 mg) and vitamin D (400-1200 IU). Primary endpoint: difference in percentage change from baseline in bone mineral density (BMD) at the lumbar spine (LS) at 12 months. Secondary endpoints: percentage changes in BMD at total hip (TH) and femoral neck (FN), relative changes in bone turnover markers (ß-CTx and P1NP), and overall safety. FINDINGS: In the treatment subpopulation, ZOL increased LS BMD by 4.7% vs. 3.3% for RIS and at TH the percentage changes were 1.8% vs. 0.2%, respectively. In the prevention subpopulation, bone loss was prevented by both treatments. At LS the percentage changes were 2.5% vs. -0.2% for ZOL vs. RIS and at TH the percentage changes were 1.1% vs. -0.4%, respectively. ZOL significantly increased lumbar spine BMD more than RIS at Month 12 in both the prevention population (p=0.0024) and the treatment subpopulation (p=0.0232) in men. In the treatment subpopulation, ZOL demonstrated a significantly greater reduction in serum ß-CTx and P1NP relative to RIS at all time-points. In the prevention subpopulation, ZOL significantly reduced ß-CTx at all time-points, and P1NP at Month 3 (p=0.0297) only. Both treatments were well tolerated in men, albeit with a higher incidence of influenza-like illness and pyrexia events post-infusion with ZOL. INTERPRETATION: Once-yearly ZOL preserves or increases BMD within 1 year to a greater extent than daily RIS in men receiving glucocorticoid therapy.

The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT).

Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.

Once-yearly zoledronic acid in older men compared with women with recent hip fracture.

OBJECTIVES: To assess the efficacy of once-yearly zoledronic acid (ZOL) 5 mg in increasing bone mineral density (BMD) in men with a recent hip fracture participating in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once- Yearly Recurrent Fracture Trial and to compare the efficacy with that in women from the same study. DESIGN: Randomized, placebo-controlled, double-blind trial. SETTING: International multicenter. PARTICIPANTS: Five hundred and eight men and 1,619 women within 90 days of surgical repair of low-trauma hip fracture in the same study (for comparison). INTERVENTION: Once-yearly intravenous (IV) ZOL 5 mg (n = 248) or placebo (n = 260), loading dose of vitamin D, daily calcium, and vitamin D supplements. MEASUREMENT: Changes in BMD. RESULTS: Percentage change from baseline in total hip BMD at Months 12 and 24 was significantly higher with ZOL than with placebo (between-group difference, 2.0%, P = .003, and 3.8%, P = .002, respectively). Percentage change from baseline in femoral neck BMD at Month 24 was significantly higher with ZOL than with placebo (3.8%, P = .003). The BMD benefit was comparable with that observed in women in this study. New clinical fractures occurred in 36 (7.1%) participants (ZOL, n = 16; placebo, n = 20; P = .64). The ZOL safety profile was comparable with that of placebo, with no significant differences in cardiovascular or long-term renal function and a trend toward lower mortality in ZOL-treated men. CONCLUSION: Once-yearly IV ZOL 5 mg increases bone mass at the hip and femoral neck in men within 90 days of repair of a low-trauma hip fracture. Increases were of a similar magnitude to those observed in women in the same study.

Subtrochanteric fractures in bisphosphonate-naive patients: results from the HORIZON-recurrent fracture trial.

Our purpose was to characterize the risks of osteoporosis-related subtrochanteric fractures in bisphosphonate-naive individuals. Baseline characteristics of patients enrolled in the HORIZON-Recurrent Fracture Trial with a study-qualifying hip fracture were examined, comparing those who sustained incident subtrochanteric fractures with those sustaining other hip fractures. Subjects were bisphosphonate-naive or had a bisphosphonate washout period of 6-24 months and subsequently received an annual infusion of zoledronic acid 5 mg or placebo after low-trauma hip-fracture repair. In total, 2,127 men and women were included. Of the qualifying hip fractures, 5.2% were subtrochanteric, 54.8% femoral neck, 33.0% intertrochanteric, and 7.1% other (generally complex fractures of mixed type). Significant baseline (pre-hip fracture) differences were seen between index hip-fracture types, with the percentage of patients with extreme mobility problems being twofold higher in patients with index subtrochanteric fracture (9.9%) compared to other patients. The distribution of hip-fracture types was similar between the treatment groups at baseline. No patients with index subtrochanteric fractures and six patients with other qualifying hip fractures reported prior bisphosphonate use. Only one further subtrochanteric fracture occurred in each treatment group over an average 2-year patient follow-up. Subtrochanteric fractures are not uncommon in bisphosphonate-naive patients. Extreme difficulties with mobility may be a unique risk factor predisposing to development of incident subtrochanteric fractures rather than other types of hip fracture. In patients with recent hip fracture who received zoledronic acid therapy, the incidence of new subtrochanteric fractures was too small to draw any meaningful conclusions.

A single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 years.

Two trials have shown that a single 5-mg infusion of zoledronic acid achieves much higher response rates in Paget disease of bone than risedronate. The duration of this effect is unknown. We have conducted an open follow-up of responders from the two trials (152 originally treated with zoledronic acid, 115 with risedronate) out to 6.5 years without further intervention. Endpoints were times to relapse (ie, return of serum total alkaline phosphatase activity to within 20% of the pretreatment value) or loss of response (response = normalization of alkaline phosphatase or 75% or greater reduction in its excess). Bone turnover markers were lower in the zoledronic acid group throughout follow-up, with mean alkaline phosphatase (ALP) remaining within the reference range in these patients, whereas the mean in the risedronate group was above normal from 1 year. Relapse rates were substantially greater in the risedronate group (23 of 115, 20%) than in those treated with zoledronic acid (1 of 152, 0.7%, p < .001), and loss of response occurred in 19 (12.5%) zoledronic acid patients compared with 71 (62%) risedronate patients (p < .0001). Risk ratios for relapse and loss of response in zoledronic acid patients were 0.02 [95% confidence interval (CI) 0.00-0.18] and 0.12 (95% CI 0.07-0.19), respectively. Changes from baseline in quality of life, assessed using SF-36 scores, were more positive in the zoledronic acid group across the follow-up period (p = .01). Bone markers at 6 months were predictive of response duration. These data demonstrate an unprecedented duration of remission of Paget disease following treatment with zoledronic acid, accompanied by an improved quality of life.

Health-related quality of life and treatment of postmenopausal osteoporosis: results from the HORIZON-PFT.

Osteoporosis-related fractures are associated with reductions in health-related quality of life (HRQL). We examined the benefits of zoledronic acid (ZOL) on HRQL in patients sustaining vertebral and clinical fractures from HORIZON-Pivotal Fracture Trial using mini-Osteoporosis quality of life Questionnaire (OQLQ). In this multicenter, double-blind, placebo-controlled trial, 1434 patients from a cohort of postmenopausal women with osteoporosis (mean age 73years) were randomized to receive annual infusions of ZOL 5mg or placebo for 3years. Baseline HRQL scores were comparable between ZOL and placebo groups based on the presence or absence of fractures, with exception of prevalent vertebral fractures where patients (irrespective of the treatment group) had lower baseline HRQL scores than those without prevalent vertebral fractures. Greater number of prevalent vertebral fractures was associated with lower baseline HRQL (p<0.001). No significant difference between ZOL and placebo in the overall summary score was observed but a significant benefit was noted in certain domains with ZOL, especially in patients sustaining incident clinical fractures. Improvements in HRQL were marked at first assessment after a morphometric vertebral fracture with significant differences favouring ZOL in pain (p=0.0115), standing pain (p=0.0125)), physical (lifting, p=0.0333) and emotional function (fear of fractures, p=0.0243; fear of falls, p=0.0075) but not for activities of daily living or leisure domains. HRQL is reduced in patients with vertebral fractures. Treatment with ZOL over 3years was associated with improvements in specific domains of quality of life vs. placebo, particularly in patients sustaining incident fractures.

Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial.

RATIONALE: Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial. OBJECTIVES: Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP. METHODS: A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours. MEASUREMENTS AND MAIN RESULTS: Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups. CONCLUSIONS: Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity.

Clinical risk factors for recurrent fracture after hip fracture: a prospective study.

Additional fractures after hip fracture are common, but little is known about the risk factors associated with these events. We determined the clinical risk factors associated with fracture following a low-trauma hip fracture and whether clinical risk factors for subsequent fracture were modified by zoledronic acid (ZOL). In this post hoc analysis of the HORIZON Recurrent Fracture trial, 2,127 men and women were randomized within 90 days of surgical hip fracture repair to receive intravenous ZOL 5 mg yearly or placebo. All patients received a loading dose of vitamin D and daily oral calcium and vitamin D supplements. In the multivariable model age, sex, BMI, femoral neck T score, and one or more fall risk factors were significant predictors of subsequent fracture. Race, history of prior fracture other than the index hip fracture, T score < -2.5 as a dichotomous variable, and type of index hip fracture were not associated with a different risk of subsequent fractures. Treatment with ZOL did not modify the impact of these risk factors. Well-established risk factors for fracture risk such as age, sex, BMI, and fall risk factors will also contribute to fracture risk in patients who have already suffered a hip fracture, while other prior fractures and T score < -2.5 are not predictive of subsequent fractures. Baseline risk factors in hip fracture patients were predictive of fracture in both ZOL- and placebo-treated participants, and there is no difference in the risk of subsequent fractures based on index hip fracture type.