Efficacy and safety of migalastat in a Japanese population: a subgroup analysis of the ATTRACT study.

BACKGROUND: Fabry disease is a progressive X-linked lysosomal disorder. In this subgroup analysis of the global phase III ATTRACT study, the efficacy and safety of oral migalastat, a pharmacologic chaperone, were investigated in Japanese patients with Fabry disease. METHODS: Patients were randomly assigned to receive migalastat (150 mg every other day) or to continue biweekly enzyme replacement therapy infusions (ERT; agalsidase alfa 0.2 mg/kg or agalsidase beta 1.0 mg/kg) for 18 months followed by a 12-month open-label extension during which all patients received migalastat. End points included glomerular filtration rate (estimated and measured), left ventricular mass index (LVMi), composite clinical outcomes, leukocyte alpha-galactosidase A activity, plasma globotriaosylsphingosine (lyso-Gb3), and safety. RESULTS: Data from 7 Japanese patients (migalastat, 5; ERT, 2), mean age 55 years, with high disease burden, were analyzed. All patients in the migalastat group completed the open-label comparison and extension periods. At 18 months, efficacy in the Japanese patient population was similar to that in the overall ATTRACT population. Migalastat treatment increased leukocyte alpha-galactosidase A activity, stabilized renal function, and decreased LVMi. Plasma lyso-Gb3 levels remained low and stable. Additionally, the long-term extension study showed that efficacy of migalastat was maintained for up to 48 months. Migalastat was safe and well tolerated in the Japanese patients, as in the overall ATTRACT population. CONCLUSION: Migalastat can be used to treat Japanese patients with Fabry disease with GLA mutations amenable to migalastat according to the dosage and administration approved in other countries. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov, NCT01218659 and NCT02194985.

AN OPEN-LABEL EXTENSION STUDY OF PARATHYROID HORMONE RHPTH(1-84) IN ADULTS WITH HYPOPARATHYROIDISM.

OBJECTIVE: Hypoparathyroidism is characterized by inadequate parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, and bone abnormalities. Adults with hypoparathyroidism treated with recombinant human PTH, rhPTH(1-84), in the 24-week, phase III REPLACE study maintained serum calcium despite reductions in oral calcium and active vitamin D. This study assessed the long-term efficacy and safety of rhPTH(1-84) for hypoparathyroidism. METHODS: This was a 24-week, open-label, flexible-dose extension study of REPLACE (REPEAT) conducted in 3 outpatient centers in Hungary. Patients who previously completed or enrolled in REPLACE received 50 µg/day rhPTH(1-84), escalated to 75 and then to 100 µg/day, if needed, to reduce active vitamin D and oral calcium. The primary endpoint was ≥50% reduction in oral calcium (or ≤500 mg/day) and active vitamin D (or calcitriol ≤0.25 µg/day or alfacalcidol ≤0.50 µg/day) with normocalcemia. RESULTS: Twenty-four patients (n = 16 previously treated with rhPTH[1-84]; n = 8 rhPTH[1-84]-naïve) were enrolled and completed the study. At Week 24, 75% of patients (95% confidence interval [CI], 53.3-90.2%) achieved the study endpoint; 58% eliminated oral calcium and active vitamin D. Urinary calcium, serum phosphate, and calcium × phosphate (Ca × P) product decreased by Week 24. Mean serum bone turnover markers increased with rhPTH(1-84). Treatment-emergent adverse events (TEAEs) were reported by 92% of patients. No serious adverse events (AEs) occurred. CONCLUSION: This study used a simplified treatment algorithm intended to better mimic typical clinical practice and demonstrated the extended efficacy and safety of rhPTH(1-84) in patients with hypoparathyroidism and confirmed the REPLACE findings. Sustained rhPTH(1-84) efficacy up to 48 weeks was observed despite treatment interruption between studies.

Understanding the burden of illness associated with hypoparathyroidism reported among patients in the PARADOX study.

OBJECTIVE: Hypoparathyroidism is a rare disease caused by lack of parathyroid hormone (PTH) leading to hypocalcemia, hyperphosphatemia, and a variety of symptoms. This study aimed to quantify the clinical and social burden of illness from the perspective of affected patients. METHODS: A web-based instrument was developed with input from patients, clinical experts, and the Hypoparathyroidism Association. Qualifying participants were ≥18 years old, diagnosed with hypoparathyroidism for ≥6 months, and U.S. residents. Questions focused on demographics, diagnosis perceptions, current attitudes, medical management, current symptoms, acute episodes, comorbidities, personal life, and employment. RESULTS: A total of 374 adults (mean age, 49 ± 12 years; female, 85%) with hypoparathyroidism (mean duration, 13 ± 12 years; severe condition, 30.5%) completed the survey. Patients reported visiting a mean of 6 ± 8 physicians before and after their diagnosis. The majority strongly agreed with feeling unprepared to manage the condition at diagnosis (56%), that controlling their hypoparathyroidism is harder than expected (60%), and that they were concerned about long-term complications of their current medications (75%). More than 10 symptoms were experienced by 72% of patients in the preceding 12 months, despite current management regimens. Symptoms were experienced for a mean of 13 ± 9 hours/day. Hospital stays or emergency department visits were required by 79% of patients. 45% reported significant interference with their lives, 85% reported an inability to perform household activities, and 20% experienced a disease-associated change in employment status. CONCLUSION: Patients with hypoparathyroidism have a high burden of illness and experience a broad spectrum of symptoms, with a multidimensional impact on their lives.

Wound closure in epidermolysis bullosa: data from the vehicle arm of the phase 3 ESSENCE Study.

BACKGROUND: Chronic wounds are a fundamental issue for patients with epidermolysis bullosa (EB). Herein, we assess the natural history of wound closure in patients with EB who were randomly assigned to the vehicle-control arm of the multicenter, randomized, double-blind, phase 3 ESSENCE (NCT02384460) trial. METHODS: ESSENCE was designed to assess the efficacy and safety of a topical cream formulation of 6% allantoin (SD-101 6%) vs vehicle (SD-101 0%) in patients ≥1 month old who had a diagnosis of EB (simplex, recessive dystrophic, or intermediate junctional) and a target wound 10-50 cm2 present for ≥21 days. Time to complete target wound closure and the proportion of patients with target wound closure over time were analyzed overall and by parameters including patient age and baseline body surface area index (BSAi) of total wound burden (< 5% and ≥ 5%). Changes in BSAi of lesional skin, pain, and itching were also assessed. RESULTS: The vehicle-control arm included 87 patients. Mean (standard deviation [SD]) time to target wound closure within 3 months was 53.6 (28.6) days, with a range of 14 to 142 days. The proportion of patients with target wound closure increased over time from 7.1% at day 14 to 53.6% at month 3. Mean (SD) changes from baseline in BSAi of total wound burden and BSAi of lesional skin at month 3 were -2.3% (6.3) and -5.0% (13.5) of total body coverage, respectively. Reductions in pain and itching were observed at day 7 and maintained for 3 months. Faster healing times and a greater proportion of patients with wound closure were observed in patients aged 1 month to < 2 years; those with wounds < 30 days old, and in those with BSAi of total body wound burden < 5%. CONCLUSIONS: Treatment response observed in the vehicle-control arm of the ESSENCE study was unexpectedly high and may have been due to unforeseen benefits of vehicle or enhanced wound care provided by the clinical trial staff. These observations will help inform the study design of future trials in patients with EB. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02384460 ; Date of registration: February 13, 2015; First participant enrollment: March 11, 2015.

Efficacy and tolerability of the investigational topical cream SD-101 (6% allantoin) in patients with epidermolysis bullosa: a phase 3, randomized, double-blind, vehicle-controlled trial (ESSENCE study).

BACKGROUND: Epidermolysis bullosa (EB) is a rare genetic disorder that manifests as blistering and/or skin erosion. There is no approved treatment for EB; current standard of care consists of wound and pain management. SD-101 6% is a topical cream containing 6% allantoin that was developed for treating skin lesions in patients with EB. The aim of this phase 3, multicenter, randomized, double-blind, vehicle-controlled study was to assess the efficacy and safety of SD-101 6% cream versus vehicle (0% allantoin) on lesions in patients with EB. METHODS: Eligible patients were ≥1 month old, had a diagnosis of EB (simplex, recessive dystrophic, or intermediate junctional) and a target wound 10-50 cm2 in size that was present for ≥21 days. Patients were randomly assigned to SD-101 6% cream or vehicle, which was applied topically once a day to the entire body for 3 months. Primary efficacy endpoints were time to complete target wound closure within 3 months and the proportion of patients who experienced complete target wound closure within 3 months. Post hoc subgroup analyses were conducted by patient age and in those with body surface area index of total body wound burden ≥5% at baseline. RESULTS: In total, 169 patients were enrolled and randomly assigned to SD-101 6% (n = 82) or vehicle (n = 87). Baseline demographics and disease characteristics were similar between treatment groups. There were no statistically significant differences between treatment groups in time to target wound closure (hazard ratio, 1.004; 95% confidence interval [CI] 0.651, 1.549; P = 0.985) or proportion of patients with complete target wound closure within 3 months (odds ratio [95% CI], 0.733 [0.365, 1.474]; nominal P = 0.390). A positive trend toward faster wound closure with SD-101 6% versus vehicle was observed in patients aged 2 to <12 years and those with total body wound burden ≥5% at baseline. SD-101 6% cream was well tolerated. CONCLUSIONS: SD-101 6% cream for treatment of EB-associated lesions was not more effective than vehicle in shortening the time to complete target wound closure or achieving complete target wound closure within 3 months. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02384460; Date of trial registration, February 13, 2015; First participant enrolled, March 11, 2015.

The challenges of living with and managing epidermolysis bullosa: insights from patients and caregivers.

BACKGROUND: Little information is available regarding the burden of living with and managing epidermolysis bullosa, including the distinct challenges faced by patients with different disease types/subtypes. METHODS: A 90-question/item survey was developed to collect demographics, diagnostic data, management practices, and burden of illness information for patients with epidermolysis bullosa living in the United States. Recruitment was conducted via email and social media in partnership with epidermolysis bullosa patient advocacy organizations in the United States, and the survey was conducted via telephone interview by a third-party health research firm. Respondents aged ≥ 18 years with a confirmed diagnosis of epidermolysis bullosa or caring for a patient with a confirmed diagnosis of epidermolysis bullosa were eligible to participate in the survey. RESULTS: In total, 156 responses were received from patients (n = 63) and caregivers (n = 93) representing the epidermolysis bullosa types of simplex, junctional, and dystrophic (subtypes: dominant and recessive). A large proportion of patients (21%) and caregivers (32%) reported that the condition was severe or very severe, and 19% of patients and 26% of caregivers reported a visit to an emergency department in the 12 months prior to the survey. Among the types/subtypes represented, recessive dystrophic epidermolysis bullosa results in the greatest wound burden, with approximately 60% of patients and caregivers reporting wounds covering > 30% of total body area. Wound care is time consuming and commonly requires significant caregiver assistance. Therapeutic options are urgently needed and reducing the number and severity of wounds was generally ranked as the most important treatment factor. CONCLUSIONS: Survey responses demonstrate that epidermolysis bullosa places a considerable burden on patients, their caregivers, and their families. The limitations caused by epidermolysis bullosa mean that both patients and caregivers must make difficult choices and compromises regarding education, career, and home life. Finally, survey results indicate that epidermolysis bullosa negatively impacts quality of life and causes financial burden to patients and their families.

Effects of parathyroid hormone rhPTH(1-84) on phosphate homeostasis and vitamin D metabolism in hypoparathyroidism: REPLACE phase 3 study.

In hypoparathyroidism, inappropriately low levels of parathyroid hormone lead to unbalanced mineral homeostasis. The objective of this study was to determine the effect of recombinant human parathyroid hormone, rhPTH(1-84), on phosphate and vitamin D metabolite levels in patients with hypoparathyroidism. Following pretreatment optimization of calcium and vitamin D doses, 124 patients in a phase III, 24-week, randomized, double-blind, placebo-controlled study of adults with hypoparathyroidism received subcutaneous injections of placebo or rhPTH(1-84) (50 µg/day, titrated to 75 and then 100 µg/day, to permit reductions in oral calcium and active vitamin D doses while maintaining serum calcium within 2.0-2.2 mmol/L). Predefined endpoints related to phosphate homeostasis and vitamin D metabolism were analyzed. Serum phosphate levels decreased rapidly from the upper normal range and remained lower with rhPTH(1-84) (P < 0.001 vs. placebo). At week 24, serum calcium-phosphate product was lower with rhPTH(1-84) vs. placebo (P < 0.001). rhPTH(1-84) treatment resulted in significant reductions in oral calcium dose compared with placebo (P < 0.001) while maintaining serum calcium. After pretreatment optimization, baseline serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) levels were within the normal range in both groups. After 24 weeks, 1,25(OH)2D levels were unchanged in both treatment groups, despite significantly greater reductions in active vitamin D dose in the rhPTH(1-84) group. In hypoparathyroidism, rhPTH(1-84) reduces serum phosphate levels, improves calcium-phosphate product, and maintains 1,25(OH)2D and serum calcium in the normal range while allowing significant reductions in active vitamin D and oral calcium doses.

Clinical experience with perindopril in African-American hypertensive patients: a large United States community trial.

BACKGROUND: The prevalence of hypertension is greater in African Americans, and management of this condition presents challenges for practicing physicians. METHODS: The effectiveness and safety of perindopril was evaluated in hypertensive African-American patients (n = 1412) and hypertensive white patients (n = 7745) who had participated in a large United States community trial. Patients received perindopril 4 mg once daily for 6 weeks. Based on physicians' clinical judgment at week 6, the dose was either maintained or increased to 8 mg for an additional 6 weeks. RESULTS: Reduction of blood pressure (BP) was significant with perindopril monotherapy (4 to 8 mg once daily) in African Americans and whites (P <.001). The magnitude of BP reduction was significantly more in whites (P <.001). Up-titration of perindopril achieved additional BP reduction in both ethnic groups (P <.001). Control of BP (<140/90 mm Hg) in elderly (>65 years of age) and diabetic African-Americans subgroups was achieved in 32.1% and 31.6%, respectively. Perindopril was safe and well tolerated. CONCLUSIONS: Perindopril monotherapy is effective and is a viable initial therapeutic option as an antihypertensive agent in African-American individuals with hypertension.

Clinical experience with perindopril in elderly hypertensive patients: a subgroup analysis of a large community trial.

OBJECTIVE: To evaluate the effectiveness and safety of perindopril in a subgroup of 3010 elderly (> or =65 years) hypertensive patients, who participated in a large US general practice-based community trial. METHODS: All patients received open-label perindopril 4 mg once a day for 6 weeks. After 6 weeks the dosage was either maintained (group I) or increased to 8 mg/day (group II) based on the physician's assessment of blood pressure (BP) response. Patients were then followed for another 6 weeks for a total study duration of 12 weeks. RESULTS: Demographic and baseline clinical characteristics revealed a higher proportion of women, longer duration of hypertension and higher baseline systolic BP (SBP) among elderly than young (<65 years, n = 7332) hypertensive patients. A clinically relevant BP reduction of similar magnitude was obtained in elderly and young patients with perindopril monotherapy. At week 12, the mean reduction in BP from baseline was 18.4/8.7 mm Hg in the elderly and 17.5/11.3 mm Hg in the young. Elderly patients with hypertension not responding adequately to the 4 mg/day dosage at week 6 had a BP reduction of 6.3/3.6 mm Hg (group II). Up-titration to an 8 mg/day dosage for another 6 weeks gave an additional 8.9/3.5 mm Hg reduction resulting in a total reduction of 15.2/7.1 mm Hg from baseline. A similar magnitude of increase in response to up-titration of perindopril was seen in young patients. BP control (<140/90 mm Hg) on perindopril monotherapy was achieved in 41.4% of elderly and 51.9% of young patients. In both age groups, up-titration to an 8.0 mg/day dosage in group II patients increased BP control by approximately 5-fold at week 12 (28.2% in the elderly and 36.4% in the young). A similar increased response on BP reduction and BP control (<140/90 mm Hg) with up-titration was seen in elderly subgroups of African American and diabetic patients. The 7th Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure recommended target goal of <130/80 mm Hg was achieved with perindopril monotherapy in 15.6% of hypertensive diabetic patients. Perindopril reduced BP effectively and safely in very elderly (> or =75 years) hypertensive patients. Perindopril was well tolerated in elderly patients including high-risk groups. The incidence of cough (7-10%), the most common symptom, was similar in all age groups. The low incidence of postural hypotension (< or =0.2%) observed in the elderly and very elderly further supports the good tolerance and safety profile of the drug. Data analysis from this study suggests that community physicians, in general, are less aggressive in controlling BP in the elderly and more inclined to treat or control diastolic BP than SBP. CONCLUSION: Perindopril treatment is effective and well tolerated in elderly patients with hypertension.

Antihypertensive utility of perindopril in a large, general practice-based clinical trial.

The authors evaluated, in a community-based open-label trial, the effectiveness and safety of perindopril in 13,220 US hypertensive patients and studied how physicians adhere to hypertension treatment guidelines. Patients received perindopril 4 mg q.d. for 6 weeks. Based on physicians perception of blood pressure response, the patient was either maintained on 4 mg or the dose was increased to 8 mg for an additional 6 weeks. From baseline to week 12, the mean sitting blood pressure significantly declined from 156.9/94.5 mm Hg to 139.2/84.0 mm Hg. Further dose titration resulted in a clinically significant reduction in blood pressure in all patients with inadequate response on 4 mg at week 6. Blood pressure control (<140/<90 mm Hg) was achieved at 12 weeks in 48.8% patients. The subpopulation analyses demonstrated that perindopril monotherapy was effective in both men and women, in patients of all ethnicities, and in patients <65 and > or =65 years of age. Perindopril was safe and well tolerated in all hypertensive subgroups including high-risk patients. Physicians were more attuned to controlling diastolic than systolic blood pressure, and their adherence to the treatment guidelines was found to be not optimal.

Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1-84) in patients with hypoparathyroidism: an open-label, single-dose, phase I study.

BACKGROUND: Impaired mineral homeostasis affecting calcium, phosphate, and magnesium is a result of parathyroid hormone (PTH) deficiency in hypoparathyroidism. The current standard of treatment with active vitamin D and oral calcium does not control levels of these major minerals. Recombinant full-length human PTH 1-84 (rhPTH[1-84]) is being developed for the treatment of hypoparathyroidism. OBJECTIVE: The goal of this study was to investigate the pharmacokinetics and pharmacodynamics of a single subcutaneous injection of rhPTH(1-84) in patients with hypoparathyroidism. METHODS: This was an open-label, dose-escalating study of single subcutaneous administration of 50 µg and then 100 µg of rhPTH(1-84). Enrolled patients (age range, 25-85 years) had ≥12 months of diagnosed hypoparathyroidism defined according to biochemical evidence of hypocalcemia with concomitant low-serum intact PTH and were taking doses ≥1000 mg/d of oral calcium and ≥0.25 µg/d of active vitamin D (oral calcitriol). The patient's prescribed dose of calcitriol was taken the day preceding but not on the day of or during the 24 hours after rhPTH(1-84) administration. Each patient received a single 50-µg rhPTH(1-84) dose, had at least a 7-day washout interval, and then received a single 100-µg rhPTH(1-84) dose. The following parameters were assessed: plasma PTH; serum and urine total calcium, magnesium, phosphate, and creatinine; and urine cyclic adenosine monophosphate. RESULTS: After administration of rhPTH(1-84) 50 µg (n = 6) and 100 µg (n = 7), the approximate t½ was 2.5 to 3 hours. Plasma PTH levels increased rapidly, then declined gradually back to predose levels at ~12 hours. The median AUC was similar with calcitriol and rhPTH(1-84) for serum 1,25-dihydroxyvitamin D (calcitriol, 123-227 pg · h/mL; rhPTH[1-84], 101-276 pg · h/mL), calcium (calcitriol, 3.3-3.7 mg · h/dL; rhPTH[1-84], 3.3-7.6 mg · h/dL), and magnesium (calcitriol, 0.7-0.9 mg · h/dL; rhPTH[1-84], 1.3-2.8 mg · h/dL). In contrast, the median AUC for phosphate was strongly negative with rhPTH(1-84) (calcitriol, -1.0 to 0.8 mg · h/dL; rhPTH[1-84], -21.3 to -26.5 mg · h/dL). Compared with calcitriol, rhPTH(1-84) 50 µg reduced 24-hour calcium excretion and calcium-to-creatinine ratios by 12% and 23%, respectively, and rhPTH(1-84) 100 µg reduced them by 26% and 27%. There was little overall impact on urine magnesium levels. Compared with calcitriol, rhPTH(1-84) 50 µg increased urinary phosphate excretion and phosphate-to-creatinine ratios by 53% and 54%, respectively, and rhPTH(1-84) 100 µg increased them by 45% and 42%. Urine cyclic adenosine monophosphate-to-creatinine ratio increased with rhPTH(1-84) by 2.3-fold (50 µg) and 4.4-fold (100 µg) compared with calcitriol. CONCLUSIONS: PTH replacement therapy with rhPTH(1-84) regulated mineral homeostasis of calcium, magnesium, phosphate, and vitamin D metabolism toward normal in these study patients with hypoparathyroidism.

Prevalence and incidence of hypoparathyroidism in the United States using a large claims database.

Hypoparathyroidism is a rare endocrine disorder whose incidence and prevalence have not been well defined. This study aimed to 1) estimate the number of insured adult patients with hypoparathyroidism in the United States and 2) obtain physician assessment of disease severity and chronicity. Prevalence was estimated through calculation of diagnoses of hypoparathyroidism in a large proprietary health plan claims database over a 12-month period from October 2007 through September 2008 and projected to the US insured population. Incidence was also calculated from the same database by determining the proportion of total neck surgeries resulting in either transient (≤6 months) or chronic (>6 months) hypoparathyroidism. A physician primary market research study was conducted to assess disease severity and determine the percentage of new nonsurgical patients with hypoparathyroidism. Incidence data were entered into an epidemiologic model to derive an estimate of prevalence. The diagnosis-based prevalence approach estimated 58,793 insured patients with chronic hypoparathyroidism in the United States. The surgical-based incidence approach yielded 117,342 relevant surgeries resulting in 8901 cases over 12 months. Overall, 7.6% of surgeries resulted in hypoparathyroidism (75% transient, 25% chronic). The prevalence of chronic hypoparathyroidism among insured patients included in the surgical database was estimated to be 58,625. The physician survey found that 75% of cases treated over the past 12 months were reported due to surgery and, among all thyroidectomies and parathyroidectomies and neck dissections performed in a year, 26% resulted in transient hypoparathyroidism and 5% progressed to a chronic state. In conclusion, the two claims-based methods yielded similar estimates of the number of insured patients with chronic hypoparathyroidism in the United States (~58,700). The physician survey was consistent with those calculations and confirmed the burden imposed by hypoparathyroidism.

Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study.

BACKGROUND: Hypoparathyroidism results in impaired mineral homoeostasis, including hypocalcaemia and hyperphosphataemia. Treatment with high-dose oral calcium and active vitamin D does not provide adequate or consistent control of biochemical indices and can lead to serious long-term complications. We aimed to test the efficacy, safety, and tolerability of once-daily recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) in adults with hypoparathyroidism. METHODS: In this double-blind, placebo-controlled, randomised phase 3 study (REPLACE), we recruited patients with hypoparathyroidism (≥ 18 months duration) aged 18-85 years from 33 sites in eight countries. After an optimisation period, during which calcium and active vitamin D doses were adjusted to achieve consistent albumin-corrected serum calcium, patients were randomly assigned (2:1) via an interactive voice response system to 50 µg per day of rhPTH(1-84) or placebo for 24 weeks. Active vitamin D and calcium were progressively reduced, while rhPTH(1-84) could be titrated up from 50 µg to 75 µg and then 100 µg (weeks 0-5). The primary endpoint was the proportion of patients at week 24 who achieved a 50% or greater reduction from baseline in their daily dose of oral calcium and active vitamin D while maintaining a serum calcium concentration greater than or the same as baseline concentrations and less than or equal to the upper limit of normal, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00732615. FINDINGS: Between June 23, 2009, and Feb 28, 2011, 134 eligible patients were recruited and randomly assigned to rhPTH(1-84) (n=90) or placebo (n=44). Six patients in the rhPTH(1-84) group and seven in the placebo group discontinued before study end. 48 (53%) patients in the rhPTH(1-84) group achieved the primary endpoint compared with one (2%) patient in the placebo group (percentage difference 51.1%, 95% CI 39.9-62.3; p<0.0001). The proportions of patients who had at least one adverse event were similar between groups (84 [93%] patients in the rhPTH[1-84] group vs 44 [100%] patients in the placebo group), with hypocalcaemia, muscle spasm, paraesthesias, headache, and nausea being the most common adverse events. The proportions of patients with serious adverse events were also similar between the rhPTH(1-84) group (ten [11%] patients) and the placebo group (four [9%] patients). INTERPRETATION: 50 µg, 75 µg, or 100 µg per day of rhPTH(1-84), administered subcutaneously in the outpatient setting, is efficacious and well tolerated as a PTH replacement therapy for patients with hypoparathyroidism.

Clinical experience with perindopril in patients nonresponsive to previous antihypertensive therapy: a large US community trial.

A subgroup analysis of a large US community trial was conducted to evaluate the antihypertensive efficacy and safety of perindopril, an angiotensin-converting enzyme inhibitor (ACEI), in 3159 patients who lacked blood pressure (BP) control at entry with previous antihypertensive therapy. Patients received 4 mg perindopril daily for 6 weeks. Based on physicians' assessment of BP response, the patients were then either maintained on 4 mg daily (group 1) or the dose was increased to 8 mg daily (group 2) for an additional 6 weeks. The mean baseline sitting BP was 158.2/92.9 mm Hg. Perindopril monotherapy produced a significant BP decrease from baseline of 11.6/6.5 mm Hg and 14.9/8.4 mm Hg at weeks 6 and 12, respectively. In group 1 patients, the majority of BP decrease occurred at week 6 (17.3/9.5 mm Hg) and was maintained until the end of week 12 (18.2/10.1 mm Hg). In group 2 patients, the BP decrease on the 4-mg dose was modest at week 6 by 5.2/3.1 mm Hg. However, further dose up-titration of perindopril to 8 mg resulted in a clinically significant BP decrease of 11.9/6.8 mm Hg from baseline to week 12. Significant antihypertensive effects of perindopril were also demonstrated in the special patient populations of elderly (>or=65 years), black, isolated systolic hypertension, patients with concomitant cardiovascular diseases, and patients nonresponsive to other ACEI therapy. Overall, BP control (<140/<90 mm Hg) was achieved in 40.0% of patients at week 12. Perindopril was well tolerated with cough and angioedema reported in 8.5% and 0.4% patients, respectively. Physicians assessed therapeutic response to perindopril as satisfactory in 73.8% patients who were nonresponsive to previous antihypertensive therapy. These results suggest that, in a community-based practice, perindopril monotherapy (4-8 mg/d) is an effective and safe therapeutic option in patients nonresponsive to previous antihypertensive therapy.