A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization.

STUDY QUESTION: Is the ongoing pregnancy rate with a new aqueous formulation of subcutaneous progesterone (Prolutex(®)) non-inferior to vaginal progesterone (Endometrin(®)) when used for luteal phase support of in vitro fertilization? SUMMARY ANSWER: In the per-protocol (PP) population, the ongoing pregnancy rates per oocyte retrieval at 12 weeks of gestation were comparable between Prolutex and Endometrin (41.6 versus 44.4%), with a difference between groups of -2.8% (95% confidence interval (CI) -9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support. WHAT IS KNOWN ALREADY: Luteal phase support has been clearly demonstrated to improve pregnancy rates in women undergoing in vitro fertilization (IVF). Because of the increased risk of ovarian hyperstimulation syndrome associated with the use of hCG, progesterone has become the treatment of choice for luteal phase support. STUDY DESIGN, SIZE, DURATION: This prospective, open-label, randomized, controlled, parallel-group, multicentre, two-arm, non-inferiority study was performed at eight fertility clinics. A total of 800 women, aged 18-42 years, with a BMI of ≤ 30 kg/m(2), with <3 prior completed assisted reproductive technology (ART) cycles, exhibiting baseline (Days 2-3) FSH of ≤ 15 IU/L and undergoing IVF at 8 centres (seven private, one academic) in the USA, were enrolled from January 2009 through June 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 800 women undergoing IVF were randomized after retrieval of at least three oocytes to an aqueous preparation of progesterone administered subcutaneously (25 mg daily) or vaginal progesterone (100 mg bid daily). Randomization was performed to enrol 100 patients at each site using a randomization list that was generated with Statistical Analysis Software (SAS(®)). If a viable pregnancy occurred, progesterone treatment was continued up to 12 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: Using a PP analysis, which included all patients who received an embryo transfer (Prolutex = 392; Endometrin = 390), the ongoing pregnancy rate per retrieval for subcutaneous versus vaginal progesterone was 41.6 versus 44.4%, with a difference between groups of -2.8% (95% CI -9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support. In addition, rates of initial positive ß-hCG (56.4% subcutaneous versus 59.0% vaginal; 95% CI -9.5, 4.3), clinical intrauterine pregnancy with fetal cardiac activity (42.6 versus 46.4%; 95% CI -10.8, 3.2), implantation defined as number of gestational sacs divided by number of embryos transferred (33.2 versus 35.1%; 95% CI -7.6, 4.0), live birth (41.1 versus 43.1%; 95% CI -8.9, 4.9) and take-home baby (41.1 versus 42.6%; 95% CI -8.4, 5.4) were comparable. Both formulations were well-tolerated, with no difference in serious adverse events. Analysis with the intention-to-treat population also demonstrated no difference for any outcomes between the treatment groups. LIMITATIONS, REASONS FOR CAUTION: The conclusions are limited to the progesterone dosing regimen studied and duration of treatment for the patient population examined in this study. WIDER IMPLICATIONS OF THE FINDINGS: Subcutaneous progesterone represents a novel option for luteal phase support in women undergoing IVF who for personal reasons prefer not to use a vaginal preparation or who wish to avoid the side effects of vaginal or i.m. routes of administration. STUDY FUNDING/COMPETING INTERESTS: The study was funded by Institut Biochimique SA (IBSA). CAJ, BC, ST and CJ are employees of IBSA. FH currently consults for IBSA. TRIAL REGISTRATION NUMBER: NCT00828191.

Safety and Efficacy of the FLECTOR (Diclofenac Epolamine) Topical System in Children with Minor Soft Tissue Injuries: A Phase IV Non-randomized Clinical Trial.

BACKGROUND AND OBJECTIVE: A topical formulation of diclofenac (FLECTOR diclofenac epolamine topical system (FDETS)) is approved in adults for the treatment of acute pain due to minor strains, sprains, and contusions; however, its safety and efficacy have not been investigated in a pediatric population. This study assessed the safety and efficacy of the FLECTOR (diclofenac epolamine) topical system in children. METHODS: This was an open-label, single-arm, phase IV study at ten USA-based family medicine or pediatric practices in children aged 6-16 years with a clinically significant minor soft tissue injury sustained within the preceding 96 h and at least moderate spontaneous pain on the Wong-Baker FACES® Pain Rating Scale. The FLECTOR topical system was applied twice daily until pain resolution or Day 14. The primary endpoint was local tolerability and systemic safety. Key secondary endpoints were diclofenac plasma concentrations and analgesic efficacy. RESULTS: 104 patients were enrolled; 52 were 6-11 years old, and 52 were 12-16 years old (mean age 11.6 years). The maximum tolerability score experienced by any patient was 1 (faint redness). Fourteen adverse events (none serious) in nine patients (8.7%) were considered possibly treatment-related. Reduction in pain during the study was somewhat greater for patients aged 6-11 versus 12-16 years (p < 0.011). The diclofenac plasma concentration tended to be higher in the younger age group compared with older patients: 1.83 versus 1.46 ng/mL at the first assessment and 2.49 versus 1.11 ng/mL at the last assessment (p = 0.002). CONCLUSION: The FLECTOR topical system safely and effectively provided pain relief for minor soft tissue injuries in the pediatric population, with minimal systemic nonsteroidal anti-inflammatory drug exposure and low potential risk of local or systemic adverse events. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02132247.

In this post-marketing clinical trial, the safety and efficacy at relieving pain of the FLECTOR diclofenac epolamine topical system (FDETS), a nonsteroidal anti-inflammatory drug (NSAID) formulation in a medicated patch, was assessed in a pediatric population (aged 6­16 years) with clinically significant minor soft tissue injuries. The safety and efficacy profiles in the pediatric population were consistent with previous data in adults. Both diclofenac plasma concentrations and reduction in pain during the study were greater for younger patients (aged 6­11 vs. 12­16 years), but plasma concentrations were much less than after diclofenac was taken orally in previous studies. This study shows that FDETS can safely and effectively provide pain relief for soft tissue injuries in children, with minimal systemic NSAID exposure and a low potential risk of either local or systemic adverse events.

Exploratory economic evaluation of patients with COPD on a combination product versus individual components (ipratropium bromide and albuterol).

A population-based, retrospective claims analysis was undertaken to explore the economic profile of a nebulized ipratropium and albuterol combination product (DuoNeb(R) [DN], DEY, L.P., Napa, Calif). This analysis was performed to review expenditures and resource utilization of patients with chronic obstructive pulmonary disease (COPD) who were taking DN or generic ipratropium and albuterol (dual single agents [DSA]). Cohort selection criteria applied to the PharMetrics managed care claims database yielded 1531 patients: 468 DN and 1063 DSA. Total per-member-per-month (PMPM) expenditures were $1,840.36 for DN and $2,046.73 DSA (Delta$206.37; P=.22). Emergency department (ED) costs were $36.67 for DN and $52.84 for DSA (Delta$16.17; P=.03). Differences in regression analysis adjusted least squares means between DSA and DN were $264.62 (P=.083) for total expenditures and $20.81 (P=.03) for ED costs. Resource utilization reflected expenditure observations; ED visits were 0.93 for DN and 1.33 for DSA (P<.001). Inpatient expenditures (DN $874.97, DSA $1,105.80; Delta$230.83) represented the largest portion of total costs: 45% with DN and 54% with DSA. The DN cohort was associated with statistically fewer individuals who reported interruptions (0.78 vs 0.85; P=.003). The DN cohort did not appear to be more expensive than the DSA group, was associated with statistically lower ED expenditures, and included fewer individuals with therapy interruptions. Future analyses should include clinical data to better elucidate the full impact of DN on healthcare resources and compliance in the COPD population.

S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial. [ISRCTN36233495].

BACKGROUND: S-adenosylmethionine (SAMe) is a dietary supplement used in the management of osteoarthritis (OA) symptoms. Studies evaluating SAMe in the management of OA have been limited to Non Steroidal Anti-inflammatory Drugs (NSAIDs) for comparison. The present study compares the effectiveness of SAMe to a cyclooxygenase-2 (COX-2) inhibitor (celecoxib) for pain control, functional improvement and to decrease side effects in people with osteoarthritis of the knee. METHODS: A randomized double-blind cross-over study, comparing SAMe (1200 mg) with celecoxib (Celebrex 200 mg) for 16 weeks to reduce pain associated with OA of the knee. Sixty-one adults diagnosed with OA of the knee were enrolled and 56 completed the study. Subjects were tested for pain, functional health, mood status, isometric joint function tests, and side effects. RESULTS: On the first month of Phase 1, celecoxib showed significantly more reduction in pain than SAMe (p = 0.024). By the second month of Phase 1, there was no significant difference between both groups (p < 0.01). The duration of treatment and the interaction of duration with type of treatment were statistically significant (ps < or = 0.029). On most functional health measures both groups showed a notable improvement from baseline, however no significant difference between SAMe and celecoxib was observed. Isometric joint function tests appeared to be steadily improving over the entire study period regardless of treatment. CONCLUSION: SAMe has a slower onset of action but is as effective as celecoxib in the management of symptoms of knee osteoarthritis. Longer studies are needed to evaluate the long-term effectiveness of SAMe and the optimal dose to be used.

Use of complementary and alternative medicine among the ethnic elderly.

OBJECTIVE: We sought to explore whether the elderly are high users of complementary and alternative medicine (CAM), and to determine which modalities they use. We also sought to describe patterns and positive predictors of CAM use among 3 ethnically diverse groups of community-residing elderly. DESIGN: A 7-page questionnaire was developed and translated into Spanish and Vietnamese. PARTICIPANTS: A population of 525 community-residing elderly completed personal interviews. RESULTS: Two hundred and fifty-one respondents (47.8%) reported using CAM over the past year. Dietary supplements (47.4%), chiropractic (16.3%), home remedies (15.9%), acupuncture (15.1%), and Oriental medicine (12.8%), were the most frequently cited therapies. The majority of CAM users (62.4%) did not inform their physicians that they were using it, but 58% consulted their physician for the same problem for which they used CAM. Family and friends were most relied upon for making the choice of therapy. Among the 3 ethnic groups studied, Asians were higher users of acupuncture (28%) and Oriental medicine (31%), Hispanics were higher users of dietary supplements (56%), home remedies (25%), and curanderos (8%), while white non-Hispanics were higher users of chiropractic (42%), massage (20%), vitamins (20%), diet (17%), and psychospiritual (15%) modalities. Pain was a higher indicator of CAM use among Asians, gastrointestinal problems and diabetes among Hispanics, and stress/fatigue and cardiovascular problems among white non-Hispanics. CONCLUSION: Findings indicated a high use of CAM among the elderly and emphasize the likelihood that elderly immigrants use those therapies with which they are familiar. Modalities and conditions varied with the ethnicity of respondents.

Factors affecting success rates in two concurrent clinical IVF trials: an examination of potential explanations for the difference in pregnancy rates between the United States and Europe.

OBJECTIVE: To compare a US clinical trial of gonadotropin therapy for IVF with a similar European trial to determine what factors may explain the higher clinical pregnancy rate in the US trial. DESIGN: Comparison of baseline, treatment, and outcome variables in the United States (US) and European trials. SETTING: IVF practices in the US (n=4) and Europe (n=6). PATIENT(S): 297 women undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate. RESULT(S): Clinical pregnancy rates were 43.4% in the US compared with 29.7% in Europe (p=0.016), with a live birth rate of 38.2% versus 27.6% (p=0.064). This difference in clinical pregnancy rate could not be explained by differences in the US versus Europe for number of embryos transferred (2.3 vs. 2.6) or female age (34.6 vs. 30.4). Although the starting dose of gonadotropin was higher in the US trial compared with the European trial (300 versus 225 IU), the total dose of gonadotropin was only slightly higher in the US. In multiple logistic regression analysis of 81 pretransfer variables on clinical pregnancy, the only two found to be significant predictors of outcome were baseline endometrial thickness following down-regulation and number of days of gonadotropin treatment. CONCLUSION(S): This study suggests the possibility that US pregnancy rates may be higher in part because of differences in down-regulation or gonadotropin dosing. Other factors not assessed in these studies or in national datasets likely also contribute to the difference in pregnancy rates.

Clinical efficacy of highly purified urinary FSH versus recombinant FSH in volunteers undergoing controlled ovarian stimulation for in vitro fertilization: a randomized, multicenter, investigator-blind trial.

OBJECTIVE: To compare the efficacy of highly purified human urinary follicle stimulating hormone (HP-hFSH) versus human recombinant follitropin-alpha (rFSH) in volunteers undergoing controlled ovarian stimulation for IVF. DESIGN: A randomized, controlled, investigator-blind trial. SETTING: Four assisted reproductive technology centers. PATIENT(S): One hundred fifty-two IVF patients. INTERVENTION(S): Volunteers, aged 18-39, were randomized to HP-hFSH (n = 76) versus rFSH (n = 76) at a starting dose of 300 IU in down-regulated cycles. MAIN OUTCOME MEASURE(S): Number of oocytes, clinical pregnancy rate, and live birth rate with HP-hFSH versus rFSH. RESULT(S): The total IU of gonadotropin used did not differ between the two groups. There was no difference in number of oocytes retrieved with HP-hFSH (mean = 16.3) compared with rFSH (mean = 17.1), confidence interval (CI) of difference = -3.79 to +2.18. Clinical pregnancy rate, as defined by the presence of a gestational sac, was 48.7% (CI = 37.0%-60.4%) with HP-hFSH versus 44.7% (CI = 33.3%-56.6%) with rFSH (CI of difference = -11.9% to +19.8%). Live birth rate was 38.2% (29 of 76) in both groups (CI = 27.2%-50.0%), for a difference between groups of 0.0% (CI of the difference = -15.4% to +15.4%). CONCLUSION(S): There were no statistically significant differences in mean oocyte number, clinical pregnancy rate, or live birth rate between HP-hFSH versus rFSH.

Effectiveness of four conservative treatments for subacute low back pain: a randomized clinical trial.

STUDY DESIGN: A randomized, assessor-blinded clinical trial was conducted. OBJECTIVE: To investigate the relative effectiveness of three manual treatments and back school for patients with subacute low back pain. SUMMARY OF BACKGROUND DATA: Literature comparing the relative effectiveness of specific therapies for low back pain is limited. METHODS: Among the 5925 inquiries, 206 patients met the specific admission criteria, and 200 patients randomly received one of four treatments for 3 weeks: back school, joint manipulation, myofascial therapy, and combined joint manipulation and myofascial therapy. These patients received assessments at baseline, after 3 weeks of therapy, and 6 months after the completion of therapy. The primary outcomes were evaluated using visual analog pain scales and Roland-Morris activity scales. RESULTS: All four groups showed significant improvement in pain and activity scores after 3 weeks of care, but did not show further significant improvement at the 6-month follow-up assessment. No statistically significant between-group differences were found either at the 3-week or 6-month reassessments. CONCLUSIONS: For subacute low back pain, combined joint manipulation and myofascial therapy was as effective as joint manipulation or myofascial therapy alone. Additionally, back school was as effective as three manual treatments.