Assessing the Burden of Illness Associated with Acquired Generalized Hypoactive Sexual Desire Disorder.

Background: Hypoactive sexual desire disorder (HSDD), which affects ∼10% of women in the United States, is defined as the persistent or recurrent deficiency/absence of sexual desire accompanied by personal distress. Although HSDD impacts patient quality of life and interpersonal relationships, the disorder often goes unaddressed or untreated. Recent studies of the burden of illness in women with HSDD, especially premenopausal women, are limited. Materials and Methods: A 45-minute web-based survey was designed to investigate the experience of women seeking treatment for HSDD and the impact of this disorder on several psychosocial aspects of women's lives. Women were recruited from an online panel of patients who participated in research studies for compensation. Validated questionnaires assessed sexual function (Female Sexual Function Index) and health-related quality of life (12-Item Short Form Survey [SF-12]), including mental and physical component scores. Results: A total of 530 women, aged ≥18 years, diagnosed with acquired generalized HSDD were included in the study. Premenopausal women indicated greater overall HSDD symptom burden compared with postmenopausal women. Patients with HSDD reported lower SF-12 scores compared with the general population. A multivariable regression analysis demonstrated that psychosocial factors influencing the burden of HSDD, including interference with their relationship with their partner (ß = -0.18; p < 0.005), mental and emotional well-being (ß = -0.23; p < 0.005), and household and personal activities (ß = -0.23; p = 0.02), negatively affected SF-12 mental component scores. Conclusions: HSDD symptom burden was found to be negatively and statistically significantly associated with patients' mental health; the impact was greater among premenopausal women compared with postmenopausal women.

Prespecified and Integrated Subgroup Analyses from the RECONNECT Phase 3 Studies of Bremelanotide.

Background: Hypoactive sexual desire disorder (HSDD), the most prevalent female sexual dysfunction, is characterized as persistent diminished desire for sexual activity accompanied by distress. The efficacy and safety of bremelanotide, a melanocortin receptor agonist approved by the U.S. Food and Drug Administration for treatment of acquired generalized HSDD in premenopausal women, were established in the phase 3 RECONNECT studies, two identically designed double-blind randomized placebo-controlled studies with an optional 52-week open-label extension. This report investigates efficacy of bremelanotide versus placebo according to prespecified subgroups (age, weight, body mass index [BMI], and bioavailable testosterone) in the RECONNECT studies. Materials and Methods: Patients self-administered bremelanotide 1.75 mg or placebo subcutaneously using an autoinjector, as needed, before sexual activity for 24 weeks. Efficacy was assessed using change from baseline to end-of-study for Female Sexual Function Index desire domain and Female Sexual Distress Scale-Desire/Arousal/Orgasm Item 13 for bremelanotide versus placebo. Results: Among 1202 patients included in the integrated and subgroup analyses, bremelanotide achieved statistically significant improvements in measures of increased desire and decreased distress associated with low desire across all age, weight, and BMI subgroups, and all baseline bioavailable testosterone quartiles, with few exceptions. Bremelanotide was further associated with statistically significant increases in reported sexual desire (p < 0.05) in patients not taking hormonal contraceptives, and with a numerical advantage in those taking hormonal contraceptives. Patients treated with bremelanotide experienced decreased distress compared with those in the placebo group at levels of statistical significance (p < 0.05) regardless of hormonal contraceptive use. Statistically significant improvements were observed in the presence or absence of decreased arousal, and regardless of HSDD duration. Conclusions: Bremelanotide was associated with statistically significant improvements in sexual desire and reduced distress across several prespecified subgroups, with few exceptions.

Safety Profile of Bremelanotide Across the Clinical Development Program.

Background: Bremelanotide, a melanocortin receptor agonist, is Food and Drug Administration (FDA)-approved for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. Methods: Review of bremelanotide's safety profile from the clinical development program (phases 1 through 3). Results: The clinical development program comprised 3500 subjects in 43 completed studies. In the phase 3 studies, subjects took bremelanotide for up to 18 months. The most common adverse events (AEs) were nausea (40.0% vs. 1.3%), flushing (20.3% vs. 1.3%), headache (11.3% vs. 1.9%), and injection site reactions (5.4 vs. 0.5), bremelanotide versus placebo groups, respectively, in the integrated double-blind portion of the phase 3 studies (N = 1247). Nausea was the most common reason for bremelanotide discontinuation. There were no deaths; a few subjects experienced serious AEs. Focal hyperpigmentation was rare when bremelanotide was dosed in accordance with label recommendations, but it occurred in more than one-third of subjects following up to 16 consecutive daily dosings. Small and transient but statistically significant blood pressure increases were observed during ambulatory blood pressure monitoring. Most drug-drug interactions were not clinically significant, except for interactions that lowered plasma concentrations of indomethacin and naltrexone. In the double-blind portion of the integrated phase 3 studies, 70% of the bremelanotide group proceeded to the open-label phase of the studies versus 87% of those on placebo. Conclusions: The AEs associated with bremelanotide are mostly mild to moderate. Although not deemed clinically important, bremelanotide should be used with caution in patients at risk of cardiovascular disease, and blood pressure should be well controlled during treatment. Clinical Trial Registration number: NCT02333071 [Study 301] and NCT02338960 [Study 302].

The Patient Experience of Premenopausal Women Treated with Bremelanotide for Hypoactive Sexual Desire Disorder: RECONNECT Exit Study Results.

Background: Hypoactive sexual desire disorder (HSDD) has a significant negative impact on women's overall health and relationships with their partners. Primary analyses from the RECONNECT clinical trials demonstrated statistically significant and clinically meaningful improvements in sexual desire and related distress with bremelanotide relative to placebo in premenopausal women with HSDD. Exit surveys and patient interviews were conducted to evaluate the impact of HSDD and bremelanotide treatment from the patient's perspective. Materials and Methods: Upon completion of the double-blind study but before participation in the open-label extension, up to 250 participants were recruited to complete the quantitative exit survey (17 questions). A subset of up to 90 patients was invited to participate in the telephone interview (17 questions). Patients who volunteered to participate remained blinded to study drug until the survey and interviews were completed. Results: Quantitative exit surveys were completed by 242 RECONNECT participants; 80 of these women also completed qualitative telephone exit interviews. Participants who received bremelanotide described increased feelings of sexual desire, physical arousal, and improvements in overall quality of their sexual activities in their partner relationship. In comparison, women taking placebo reported benefits that did not include the physiological responses described by women receiving bremelanotide, such as positive experiences of seeking HSDD treatment and improved communication with their partner. Conclusions: Exit surveys and patient interviews support the primary findings from RECONNECT and provide quantitative and qualitative assessments of the impact of HSDD on patients' quality of life and the patients' perspectives on the impact of bremelanotide. Clinical trial numbers NCT02333071, NCT02338960.

Reliability and validity of the elements of desire questionnaire in premenopausal women with hypoactive sexual desire disorder.

BACKGROUND: The Elements of Desire Questionnaire (EDQ) is a patient-reported outcome (PRO) measure developed to evaluate sexual desire and was included in two identically designed phase 3 clinical trials (RECONNECT) as an exploratory endpoint. The EDQ was developed based on a literature review, qualitative research with patients with hypoactive sexual desire disorder (HSDD), and input from clinical experts. This instrument is intended to be used to collect efficacy data in clinical trials evaluating potential treatments for HSDD. The objective of this study was to evaluate the measurement properties of both the monthly and daily recall versions of the EDQ during the RECONNECT trials. METHODS: Participants completed the EDQ daily version for 7 consecutive days prior to selected monthly clinic visits. The monthly recall version was completed at each monthly clinic visit. The analysis population consisted of all subjects with Female Sexual Function Index (FSFI) data at baseline and ≥ 1 follow-up visit. RESULTS: At baseline, 1144 and 676 subjects completed the monthly and daily recall EDQs, respectively. The EDQ scores had good internal consistency and test-retest reliability. Monthly and daily recall EDQ scores were correlated with FSFI-desire domain scores at baseline and month 3. Scores from the monthly and daily recall versions were also correlated. After 6 months, there was a significantly greater improvement for bremelanotide versus placebo in both the monthly and daily recall versions (both P < 0.0001). CONCLUSIONS: The results demonstrated that EDQ exhibited good reliability, validity, and sensitivity to change. Consistent with other validated PRO measures of sexual desire, the EDQ provides additional insights into sexual desire. TRIAL REGISTRATION: NCT02338960 and NCT02333071 (RECONNECT studies).

Hypoactive sexual desire disorder (HSDD) is not "female erectile dysfunction (ED)": challenges with the characterization of HSDD in women based on a systematic literature review.

Objective: Hypoactive sexual desire disorder (HSDD) in women has been viewed inaccurately by some in the medical and payer community as analogous to erectile dysfunction (ED) in men. This literature review aims to highlight the distinctions between HSDD and ED.Methods: Two systematic literature searches were conducted on the epidemiology, symptomatology and biopsychosocial outcomes of HSDD and ED. Studies published since 2007 were considered for HSDD; studies published since 2012 were considered for ED.Results: HSDD in women is primarily a central nervous system condition related to neuroendocrine factors, whereby neural pathways that regulate sexual excitation and/or inhibition appear to be involved. A combination of organic and psychogenic factors often contributes to ED. HSDD and ED are associated with similar psychological and interpersonal consequences, but affect different phases of the sexual response model (desire versus arousal) and have different pathophysiologies, therefore requiring different treatment and outcome paradigms. ED is measured by objective, physiological responses (erection and sexual function), but quantitative assessments for HSDD are more difficult because loss of desire with associated distress has to be assessed. Outcome measures used to assess ED, such as the number of satisfying sexual events, are far less informative as an endpoint for randomized clinical trials of treatments for HSDD.Conclusions: HSDD and ED are distinct conditions affecting different phases of the sexual response model, and thus require clear and unique clinical characterization and adequate communication between the health care professional and patient for appropriate diagnosis, management and treatment.

17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial.

BACKGROUND: Women with a history of spontaneous preterm birth (SPTB) are at a significantly increased risk for recurrent preterm birth (PTB). To date, only one large U.S. clinical trial comparing 17-OHPC (17-α-hydroxyprogesterone caproate or "17P") to placebo has been published, and this trial was stopped early due to a large treatment benefit. OBJECTIVE: This study aimed to assess whether 17-OHPC decreases recurrent PTB and neonatal morbidity in women with a prior SPTB in a singleton gestation. STUDY DESIGN: This was a double-blind, placebo-controlled international trial involving women with a previous singleton SPTB (clinicaltrials.gov: NCT01004029). Women were enrolled at 93 clinical centers (41 in the United States and 52 outside the United States) between 160/7 to 206/7 weeks in a 2:1 ratio, to receive either weekly intramuscular (IM) injections of 250 mg of 17-OHPC or an inert oil placebo; treatment was continued until delivery or 36 weeks. Co-primary outcomes were PTB < 35 weeks and a neonatal morbidity composite index. The composite included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, or proven sepsis. A planned sample size of 1,707 patients was estimated to provide 98% power to detect a 30% reduction in PTB < 35 weeks (30% to 21%) and 90% power to detect a 35% reduction in neonatal composite index (17%-11%) using a two-sided type-I error of 5%. Finally, this sample size would also provide 82.8% power to rule out a doubling in the risk of fetal/early infant death assuming a 4% fetal/early infant death rate. Analysis was performed according to the intention-to-treat principle. RESULTS: Baseline characteristics between the 1,130 women who received 17-OHPC and 578 women who received placebo were similar. Overall, 87% of enrolled women were Caucasian, 12% had >1 prior SPTB, 7% smoked cigarettes, and 89% were married/lived with partner. Prior to receiving study drug, 73% women had a transvaginal cervical length measurement performed and <2% had cervical shortening <25 mm. There were no significant differences in the frequency of PTB < 35 weeks (17-OHPC 11.0% vs. placebo 11.5%; relative risk = 0.95 [95% confidence interval (CI): 0.71-1.26]) or neonatal morbidity index (17-OHPC 5.6% vs. placebo 5.0%; relative risk = 1.12 [95% CI: 0.68-1.61]). There were also no differences in frequency of fetal/early infant death (17-OHPC 1.7% vs. placebo 1.9%; relative risk = 0.87 [95% CI: 0.4-1.81]. Maternal outcomes were also similar. In the subgroup of women enrolled in the United States (n = 391; 23% of all patients), although the rate of PTB < 35 weeks was higher than the overall study population, there were no statistically significant differences between groups (15.6% vs. 17.6%; relative risk = 0.88 [95% CI: 0.55, 1.40]. CONCLUSION: In this study population, 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death.

Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials.

OBJECTIVE: To evaluate the safety and efficacy of bremelanotide for the treatment of premenopausal women with hypoactive sexual desire disorder. METHODS: Two identical phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trials (RECONNECT) evaluated the safety and efficacy of bremelanotide 1.75 mg administered subcutaneously as needed in premenopausal women with hypoactive sexual desire disorder. Patients were randomized 1:1 to 24 weeks of treatment with bremelanotide or placebo. Sample size was estimated based on simulations from key endpoints in patients with hypoactive sexual desire disorder from a prior trial. Coprimary efficacy endpoints were change from baseline to end-of-study in the Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13. RESULTS: Study 301 began on January 7, 2015, and concluded on July 26, 2016. Study 302 began on January 28, 2015, and concluded on August 4, 2016. Of the 1,267 women randomized, 1,247 and 1,202 were in the safety and efficacy (modified intent-to-treat) populations, respectively. Most participants were white (85.6%), from U.S. sites (96.6%), and had a mean age of 39 years. From baseline to end-of-study, women taking bremelanotide had statistically significant increases in sexual desire (study 301: 0.30, P<.001; study 302: 0.42, P<.001; integrated studies 0.35, P<.001) and statistically significant reductions in distress related to low sexual desire (study 301: -0.37, P<.001; study 302: -0.29, P=.005; integrated studies -0.33, P<.001) compared with placebo. Patients taking bremelanotide experienced more nausea, flushing, and headache (10% or more in both studies) compared with placebo. CONCLUSIONS: Both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in premenopausal women with hypoactive sexual desire disorder. The safety profile was favorable. Most treatment-emergent adverse events were related to tolerability and the majority were mild or moderate in intensity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302). FUNDING SOURCE: Palatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder.

OBJECTIVE: To evaluate the long-term safety and efficacy of bremelanotide as treatment for hypoactive sexual desire disorder in premenopausal women. METHODS: Women who completed the 24-week double-blind core phase of RECONNECT, composed of two parallel phase 3 trials (301 and 302) examining the safety and efficacy of bremelanotide compared with placebo in premenopausal women with hypoactive sexual desire disorder, could enroll in the 52-week open-label extension, provided they had not experienced serious adverse events during the core phase. Efficacy was assessed using the coprimary endpoints from the core phase, and all adverse events were collected during the open-label extension. All statistical analyses were descriptive. RESULTS: The study 301 open-label extension began on July 17, 2015, and concluded on July 13, 2017; the study 302 open-label extension began on October 5, 2015, and concluded on June 29, 2017. Of the 856 eligible patients who completed the core phase, 684 elected to participate in the open-label extension, and 272 completed it. The most common treatment-emergent adverse events considered related to study drug were nausea (40.4%), flushing (20.6%), and headache (12.0%), and the only severe treatment-emergent adverse event experienced by more than one participant in both studies was nausea during the open-label extension. The change in Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13 from baseline to end of the open-label extension ranged from 1.25 to 1.30 and -1.4 to -1.7, respectively, for patients who received bremelanotide during the core phase, and 0.70-0.77 and -0.9, respectively, for patients who received placebo during the core phase. CONCLUSION: During the 52-week open-label extension of RECONNECT, no new safety signals were observed, and premenopausal women treated with bremelanotide exhibited sustained improvements in hypoactive sexual desire disorder symptoms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302). FUNDING SOURCE: Palatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

Female Sexual Health: Barriers to Optimal Outcomes and a Roadmap for Improved Patient-Clinician Communications.

BACKGROUND: Although sexual health can be considered a vital sign for overall health, several barriers prevent women from receiving proper medical counseling, support, and/or care for their sexual health needs and concerns. METHODS: Experts in sexual health compiled research and experience on the impediments to women receiving adequate assessment and treatment for their sexual health. Specific solutions and a roadmap for overcoming such barriers and improving patient-clinician communication are presented. RESULTS: Social stigma around female sexuality remains in Western culture and as a result, women often avoid and/or are embarrassed to discuss their sexual health with their health care professionals (HCPs). Moreover, midlife women are typically unaware or have misconceptions about conditions that may adversely impact their sexual life, such as genitourinary syndrome of menopause and hypoactive sexual desire disorder. Without understanding there may be underlying medical conditions, there is also a lack of awareness that safe and effective treatments are available. Lack of training, tools, time, and limited treatment options impede HCPs from providing women with necessary sexual health support. Educating women, training HCPs, and providing communication tools to HCPs can facilitate effective dialog between patients and HCPs. More specifically, HCPs can be trained to initiate and maintain a sexual health conversation in a manner that is comfortable for women to convey sexual health needs and concerns, and for HCPs to correctly identify, diagnose, and treat the sexual problems of their female patients. CONCLUSIONS: Solutions exist to address the barriers currently impeding patient-clinician interactions around sexual health.

Randomized trial of intravenous iron-induced hypophosphatemia.

BACKGROUND: Hypophosphatemia can complicate intravenous iron therapy, but no head-to-head trials compared the effects of newer intravenous iron formulations on risks and mediators of hypophosphatemia. METHODS: In a randomized, double-blinded, controlled trial of adults with iron deficiency anemia from February 2016 to January 2017, we compared rates of hypophosphatemia in response to a single FDA-approved course of ferric carboxymaltose (n = 1,000) or ferumoxytol (n = 997). To investigate pathophysiological mediators of intravenous iron-induced hypophosphatemia, we nested within the parent trial a physiological substudy (ferric carboxymaltose, n = 98; ferumoxytol, n = 87) in which we measured fibroblast growth factor 23 (FGF23), calcitriol, and parathyroid hormone (PTH) at baseline and 1, 2, and 5 weeks later. RESULTS: The incidence of hypophosphatemia was significantly higher in the ferric carboxymaltose versus the ferumoxytol group (<2.0 mg/dl, 50.8% vs. 0.9%; <1.3 mg/dl, 10.0% vs. 0.0%; P < 0.001), and hypophosphatemia persisted through the end of the 5-week study period in 29.1% of ferric carboxymaltose-treated patients versus none of the ferumoxytol-treated patients (P < 0.001). Ferric carboxymaltose, but not ferumoxytol, increased circulating concentrations of biologically active FGF23 (mean within-patient percentage change from baseline to week 2 peak: +302.8 ± 326.2% vs. +10.1 ± 61.0%; P < 0.001), which was significantly associated with contemporaneous hypophosphatemia, renal phosphate wasting, and decreased serum calcitriol and calcium, and increased PTH concentrations. CONCLUSIONS: Ferric carboxymaltose rapidly increases biologically active FGF23 in patients with iron deficiency anemia. Paralleling hereditary and other acquired syndromes of hypophosphatemic rickets/osteomalacia, ferric carboxymaltose-induced FGF23 elevation triggers a pathophysiological cascade of renal phosphate wasting, calcitriol deficiency, and secondary hyperparathyroidism that frequently culminates in hypophosphatemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02694978FUNDING. AMAG Pharmaceuticals, Inc.Role of the funding source: This study was supported by AMAG Pharmaceuticals, Inc. The academic investigators designed the clinical trial, performed the analyses, and authored the manuscript with input from the coauthors from AMAG Pharmaceuticals, Inc.

Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial.

Few trials have examined rates of hypersensitivity reactions (HSRs) with intravenous iron formulations used to treat iron deficiency anemia (IDA). This randomized, multicenter, double-blind clinical trial compared the safety, and efficacy of ferumoxytol versus ferric carboxymaltose (FCM), focusing on rates of HSRs and hypotension as the primary end point. Patients with IDA of any etiology in whom oral iron was unsatisfactory or intolerable received ferumoxytol (n = 997) or FCM (n = 1000) intravenously over ≥15 minutes on days 1 and 8 or 9 for total respective doses of 1.02 g and 1.50 g. Composite incidences of moderate-to-severe HSRs, including anaphylaxis, or moderate-to-severe hypotension from baseline to week 5 (primary safety end point) were 0.6% and 0.7% in the ferumoxytol and FCM groups, respectively, with ferumoxytol noninferior to FCM. No anaphylaxis was reported in either group. The secondary safety end point of incidences of moderate-to-severe HSRs, including anaphylaxis, serious cardiovascular events, and death from baseline to week 5 were 1.3% and 2.0% in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Least-squares mean changes in hemoglobin at week 5 were 1.4 g/dL and 1.6 g/dL in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Incidence of hypophosphatemia was 0.4% for ferumoxytol and 38.7% for FCM.

Comparative Bioavailability of Hydroxyprogesterone Caproate Administered via Intramuscular Injection or Subcutaneous Autoinjector in Healthy Postmenopausal Women: A Randomized, Parallel Group, Open-label Study.

PURPOSE: The purpose of this study was to evaluate the bioavailability of hydroxyprogesterone caproate (HPC) administered as a subcutaneous injection in the back of the upper arm using a prefilled autoinjector syringe with a 27-gauge needle compared with standard intramuscular injection in the gluteus maximus using a 21-gauge needle. METHODS: Healthy postmenopausal women 50 to 75 years old were randomized in a parallel group design to receive a single SC injection of 1.1 mL (275-mg total dose) of preservative-free HPC administered using an autoinjector in the back of the upper arm or a single IM injection of 1 mL (250-mg total dose) of preservative-free HPC administered in the gluteus maximus. Blood samples were collected through 1008 hours (42 days) after injection. The primary measures were the Cmax, AUC0-t, and AUC0-∞. Secondary measures were Tmax, ke, t½, and injection site reactions captured as a treatment-emergent adverse event. FINDINGS: The pharmacokinetic population consisted of 90 individuals; 45 received subcutaneous administration and 45 received intramuscular administration. Geometric mean whole blood concentrations of HPC were comparable between administration regimens. Subcutaneous administration resulted in a higher geometric mean Cmax than intramuscular administration (7.88 vs 6.91 ng/mL), but median Tmax values were comparable (48.1 vs 49.7 hours). The least square geometric mean ratios for AUC0-168), AUC0-t, and AUC0-∞ were 102.89%, 110.25%, and 113.51%, respectively, with all 90% CIs within the 80.0% to 125.0% window that defined bioequivalence. The ratio for Cmax was 113.95% with a 90% CI of 91.94% to 141.23% but with substantial overlap of individual values between administration regimens. The geometric mean t½ of HPC was 212 hours for the subcutaneous administration and 188 hours for the intramuscular administration. The most common treatment-emergent adverse event was injection site pain (subcutaneous, 37.3%; intramuscular, 8.2%), described as mild (85%) to moderate (15%). IMPLICATIONS: Administration of HPC by SC injection of 1.1 mL (275 mg) via autoinjector is bioequivalent to IM injection of 1.0 mL (250 mg). ClinicalTrials.gov identifier: NCT02940522.

Comparative safety of intravenous Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia: rationale and study design of a randomized double-blind study with a focus on acute hypersensitivity reactions.

BACKGROUND: Intravenous (IV) iron is often used to treat iron deficiency anemia in patients who are unable to tolerate or are inadequately managed with oral iron. However, IV iron treatment has been associated with acute hypersensitivity reactions. The comparative risk of adverse events (AEs) with IV iron preparations has been assessed by a few randomized controlled trials, which are most often limited by small patient numbers, which lack statistical power to identify differences in low-frequency AE such as hypersensitivity reactions. MATERIALS AND METHODS: Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia (FIRM) is a randomized, double-blind, international, multicenter, Phase III study designed to compare the safety of ferumoxytol and ferric carboxymaltose (FCM). The study includes adults with hemoglobin <12.0 g/dL (females) or <14.0 g/dL (males), transferrin saturation ≤20% or ferritin ≤100 ng/mL within 60 days of dosing, and a history of unsatisfactory or nontolerated oral iron therapy or in whom oral iron therapy is inappropriate. Patients are randomized (1:1) to ferumoxytol 510 mg or FCM 750 mg, each given intravenously on days 1 and 8. Primary end points are the incidence of moderate-to-severe hypersensitivity reactions, including anaphylaxis, and moderate-to-severe hypotension. All potential hypersensitivity and hypotensive reactions will be adjudicated by a blinded, independent Clinical Events Committee. A secondary safety end point is the composite frequency of moderate-to-severe hypersensitivity reactions, including anaphylaxis, serious cardiovascular events, and death. Secondary efficacy end points include mean change in hemoglobin and mean change in hemoglobin per milligram of iron administered from baseline to week 5. Urinary excretion of phosphorus and the occurrence of hypophosphatemia after IV iron administration will be examined as well as the mechanisms of such hypophosphatemia in a substudy. CONCLUSION: FIRM will provide data on the comparative safety of ferumoxytol and FCM, two IV iron preparations with similar dosing schedules, focusing on moderate-to-severe hypersensitivity reactions, including anaphylaxis, and moderate-to-severe hypotension. The study plans to enroll 2000 patients and is expected to complete in 2017.

Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis.

BACKGROUND: There are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra-articular recombinant human BMP-7 (bone morphogenetic protein-7) has reparative effects on cartilage, as well as on symptoms of joint pain. The objective of this study was to determine the safety and tolerability as well as dose-limiting toxicity and maximal tolerated dose of intra-articular BMP-7. The secondary objectives were to determine the effect on symptomatic responses through 24 weeks. METHODS: This was a Phase 1, double-blind, randomized, multi-center, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts in participants with knee OA. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active (intra-articular BMP-7) to placebo ratio. Eligible participants were persons with symptomatic radiographic knee OA over the age of 40. The primary objective of this study was to determine the safety and tolerability of BMP-7 including laboratory assessments, immunogenicity data and radiographic assessments. Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria. RESULTS: The mean age of participants was 60 years and 73% were female. All 33 participants who were enrolled completed the study and most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. The 1 mg BMP-7 group showed a higher frequency of injection site pain and there was no ectopic bone formation seen on plain x-rays. By week 12, most participants in both the BMP-7 and placebo groups experienced a 20% improvement in pain and overall the BMP-7 group was similar to placebo with regard to this measurement. In the participants who received 0.1 mg and 0.3 mg BMP-7, there was a trend toward greater symptomatic improvement than placebo. The other secondary endpoints showed similar trends including the OARSI responder criteria for which the BMP-7 groups had more responders than placebo. CONCLUSIONS: There was no dose limiting toxicity identified in this study. The suggestion of a symptom response, together with the lack of dose limiting toxicity provide further support for the continued development of this product for the treatment of osteoarthritis.

The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis: a long-term (>4 years) pivotal study.

STUDY DESIGN: Randomized controlled trial comparing OP-1 (rhBMP-7) with iliac crest autograft in patients with symptomatic degenerative spondylolisthesis and spinal stenosis treated with decompression and uninstrumented posterolateral arthrodesis. OBJECTIVE: To determine the safety and the clinical and radiographic efficacy of OP-1 (rhBMP-7) Putty as compared with an iliac crest bone autograft control in uninstrumented, single-level posterolateral spinal arthrodesis. SUMMARY OF BACKGROUND DATA: Preclinical and preliminary clinical data have demonstrated successful fusion and clinical outcomes with the use of OP-1 Putty in posterolateral spinal arthrodesis. No prior randomized controlled trial with adequate study power has been performed. METHODS: A total of 335 patients were randomized in 2:1 fashion to receive either OP-1 Putty or autograft in the setting of an uninstrumented posterolateral arthrodesis performed for degenerative spondylolisthesis and symptomatic spinal stenosis. Patients were observed serially with radiographs, clinical examinations, and appropriate clinical indicators, including ODI, Short-Form 36, and visual analog scale scores. Serum samples were examined at regular intervals to assess the presence of antibodies to OP-1. The primary end point, Overall Success, was analyzed at 24 months. The study was extended to include additional imaging data and long-term clinical follow-up at 36+ months. At the 36+ month time point, CT scans were obtained in addition to plain radiographs to evaluate the presence and location of new bone formation. Modified Overall Success, including improvements in ODI, absence of retreatment, neurologic success, absence of device-related serious adverse events, angulation and translation success, and new bone formation by CT scan (at 36+ months), was then calculated using the 24-month primary clinical endpoints, updated retreatment data, and CT imaging and radiographic end points. RESULTS: OP-1 Putty was demonstrated to be statistically equivalent to autograft with respect to the primary end point of modified overall success. The use of OP-1 Putty when compared to autograft was associated with statistically lower intraoperative blood loss and shorter operative times. Although patients in the OP-1 Putty group demonstrated an early propensity for formation of anti-OP-1 antibodies, this resolved completely in all patients with no clinical sequelae. CONCLUSION: OP-1 Putty is a safe and effective alternative to autograft in the setting of uninstrumented posterolateral spinal arthrodesis performed for degenerative spondylolisthesis and symptomatic spinal stenosis.

A rare cause of pituitary stalk enlargement and panhypopituitarism.

Pituitary stalk involvement is seen in a variety of medical conditions such as infectious diseases, infiltrative diseases and tumors (intracranial and metastatic). Metastatic cancer has a greater propensity to involve the infundibulum and neurohypophysis. We report a case of a 68-year-old man who presented with thickening of the stalk, panhypopituitarism, diabetes insipidus and generalized lymphadenopathy. Lymphoma was diagnosed on axillary lymph node biopsy and lymphomatous involvement of the infundibulum was suspected. Although infundibular thickening resolved and diabetes insipidus improved after chemotherapy, panhypopituitarism persisted.

Diabetes-related morbidity and mortality in a national sample of U.S. elders.

OBJECTIVE: Although the number of elders with diabetes has increased dramatically, there are few data on rates of mortality and serious complications in older populations with diabetes. To determine such rates, we conducted a population-based, nonconcurrent cohort study using claims data from the 1994-1996 Medicare 5% Standard Analytical File. RESEARCH DESIGN AND METHODS: Codes from the ICD-9 were used to identify diabetes and the following complications: amputation, lower extremity infection, gangrene, blindness, acute myocardial infarction, ischemic heart disease, stroke, and metabolic disorders. Using these codes, we assembled a cohort of 148,562 Medicare Part A and B beneficiaries who were > or = 65 years of age, who were alive on 1 January 1995, who were not in managed care in 1994, and who had a diabetes-related claim in 1994. Age-specific rates of death and complications were then calculated. RESULTS: During 24 months of follow-up, 22,044 (14.8%) elders with diabetes died. Death rates in men and women increased significantly with age. Compared with their counterparts in the general U.S. population, elders with diabetes suffered excess mortality at every age group, corresponding to an overall standardized mortality ratio of 1.41 (95% CI 1.39,1.43). The incidence of ischemic heart disease and stroke was 181.5 and 126.2 per 1,000 person-years, respectively, which was higher than the incidence of all other diabetes-related complications. CONCLUSIONS: In every age group, elders with diabetes have significantly higher all-cause mortality rates than the general population. Medicare data may be useful in monitoring trends in diabetes-related morbidity and total mortality in U.S. elders with diabetes.