Comparator-controlled Study Research Articles

P21 A Phase 3 randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability and immunogenicity of a 21-valent PCV, V116, in pneumococcal vaccine-naive adults (STRIDE-3)

Abstract Background Pneumococcal disease (PD) prevention remains an unmet medical need in adults. V116 is an investigational pneumococcal conjugate vaccine (PCV) containing the most prevalent serotypes associated with PD in adults in regions with established paediatric vaccination programmes. This Phase 3 study evaluated safety, tolerability, and immunogenicity of V116 compared with PCV20 in adults. Methods Pneumococcal vaccine-naive adults ≥18 years were eligible. Cohort 1 (≥50 years, n=2362) was stratified by age (50–64, 65–74, 75–84 and ≥85) and randomized 1:1 to receive 1 dose of V116 or PCV20, and cohort 2 (18–49 years, n=301) was randomized 2:1 to receive 1 dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured at baseline (Day 1) and 30 days post vaccination (Day 30). Primary objectives included assessment of (i) non-inferiority of immune responses for the serotypes common to V116 and PCV20 in cohort 1; (ii) superiority of serotypes unique to V116 compared with PCV20 in cohort 1; and (iii) immunobridging from adults 18–49 to adults 50–64 for all 21 serotypes in V116. Safety was evaluated by the proportion of participants with adverse events (AEs). Results V116 is non-inferior to PCV20 for the 10 serotypes common to both vaccines as measured by serotype-specific OPA geometric mean titres (GMTs) at Day 30. V116 is superior to PCV20 for 10 of 11 unique serotypes as measured by OPA GMTs at Day 30 as well as based on the proportions of participants with a ≥4-fold rise in OPA from Day 1 to Day 30. V116 elicits comparable immune responses in participants 18–49 years compared with participants 50–64 years for the 21 serotypes in V116 as assessed by serotype-specific OPA GMTs at Day 30, successfully demonstrating immunobridging. In total, 61.7% and 67.2% of participants vaccinated with V116 and PCV20, respectively, had ≥1 AE. There were no vaccine-related serious AEs or vaccine-related deaths. Conclusions V116 elicits immune responses that are non-inferior to PCV20 for the common serotypes and superior to PCV20 for 10 of 11 unique serotypes in V116 and has a safety profile comparable to PCV20. This pivotal study supports V116 as a novel population-specific vaccine for the prevention of PD in adults.

A phase 3 randomized, double-blind, comparator-controlled study to evaluate safety, tolerability and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in allogeneic hematopoietic cell transplant recipients (PNEU-STEM).

Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk for pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE™), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. Participants received 3 doses of V114 or PCV13 in one-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAXTM 23 or a fourth dose of PCV (if they experienced chronic graft versus host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at Day 90. V114 was well tolerated in allo-HCT recipients with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and higher for V114 serotypes 22F and 33F. Study results support use of V114 in allo-HCT recipients.

A Phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of V114 compared with PCV13 in healthy infants (PNEU-PED-EU-1)

BackgroundV114 (15-valent pneumococcal conjugate vaccine [PCV]) contains all serotypes in 13-valent PCV (PCV13) and additional serotypes 22F and 33F. This study evaluated safety and immunogenicity of V114 compared with PCV13 in healthy infants, and concomitant administration with DTPa–HBV–IPV/Hib and rotavirus RV1 vaccines. MethodsV114 and PCV13 were administered in a 2+1 schedule at 2, 4, and 11–15 months of age. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series (PPS), immediately prior to a toddler dose, and 30 days post-toddler dose (PTD). Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for the two additional serotypes. Results1184 healthy infants 42–90 days of age were randomized 1:1 to V114 (n = 591) or PCV13 (n = 593). Proportions of participants with solicited AEs and serious AEs were comparable between vaccination groups. V114 met pre-specified non-inferiority criteria for all 13 shared serotypes, based on the difference in proportions of participants with serotype-specific IgG concentrations ≥0.35 μg/mL (response rate; lower bound of two-sided 95% confidence interval [CI] >−10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5), and pre-specified superiority criteria for serotypes 22F and 33F (lower bound of two-sided 95% CI >10.0 for response rates and >2.0 for GMC ratios). Antibody responses to DTPa–HBV–IPV/Hib and RV1 vaccines met pre-specified non-inferiority criteria, based on antigen-specific response rates to DTPa–HBV–IPV/Hib and anti-rotavirus IgA geometric mean titers. ConclusionsAfter a 2+1 schedule, V114 elicited non-inferior immune responses to 13 shared serotypes and superior responses to the two additional serotypes compared with PCV13, with comparable safety profile. These results support the routine use of V114 in infants.Trial registration: ClinicalTrials.gov: NCT04031846; EudraCT: 2018-003787-31

P07 A Phase 3 randomized, double-blind, comparator-controlled study to evaluate safety, tolerability and immunogenicity of V114 pneumococcal vaccine in haematopoietic cell transplant recipients (PNEU-STEM)

Abstract Background Allogeneic haematopoietic cell transplant (allo-HCT) represents a definitive therapy for a variety of haematological diseases. Immunosuppressive therapy following allo-HCT and graft-versus-host disease (GVHD) render the patient susceptible to infectious complications, including invasive pneumococcal disease. Post-allo-HCT pneumococcal vaccination is recommended 3–6 months after transplant in a multi-dose series to help prevent pneumococcal disease. Objectives V114 is a 15-valent pneumococcal conjugate vaccine (PCV) approved in adults, containing all 13 serotypes in Prevnar 13™ (PCV13; contains serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) as well as epidemiologically important serotypes 22F and 33F. This study evaluated safety and immunogenicity of V114 when given to allo-HCT recipients. Methods Individuals ≥3 years of age were randomized 1:1 to receive 3 doses of V114 or PCV13 in one-month intervals starting 3–6 months after allo-HCT. At 12 months after HCT, participants received either PNEUMOVAXTM 23 or a fourth dose of PCV if they experienced chronic GVHD. All participants or their legal representatives provided informed consent at enrolment. Primary safety objective was to evaluate the proportion of participants with adverse events (AEs) within each vaccination group for 3 to <18 years old and ≥18 years old age groups. Primary immunogenicity objective was to evaluate serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) for all 15 V114 serotypes at 30 days following the third PCV dose (Day 90) in each vaccination group. A key secondary objective was to evaluate opsonophagocytic activity (OPA) geometric mean titres (GMTs) for all V114 serotypes at Day 90. Results A total of 274 subjects (14 children [3 to <18 years of age] and 260 adults ≥18 years old) were enrolled and vaccinated in the study. The proportion of participants with systemic AEs and serious AEs after any dose of study vaccine were generally comparable between intervention groups in the paediatric and adult cohorts. V114 recipients reported a higher proportion of injection-site AEs and vaccine-related systemic AEs compared with PCV13 in the adult cohort. Of all vaccinated participants, 32.4% experienced serious AEs during the study (28.8% in V114 group, 36.3% in PCV13 group). Seventeen participants (5.8% in V114 group, 6.7% in PCV13 group) died during the study. None of the deaths was determined by the investigator to be related to study vaccines. For both IgG GMCs (Table 1) and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at Day 90. Conclusions V114 was well tolerated in allo-HCT recipients with a generally comparable safety profile to PCV13 for both paediatric and adult participants. Despite the immunocompromised status of the participants, the study vaccines induced serotype-specific immunogenicity and V114 induced generally comparable responses to PCV13 by IgG GMCs and OPA for the 13 shared serotypes at Day 90. In addition, V114 induced higher antibody responses than PCV13 for serotypes unique to V114 (22F and 33F). Study results support the use of V114 in allo-HCT recipients.

A phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of catch-up vaccination regimens of V114, a 15-valent pneumococcal conjugate vaccine, in healthy infants, children, and adolescents (PNEU-PLAN)

BackgroundDespite widespread use of pneumococcal conjugate vaccines (PCVs) in children, morbidity and mortality caused by pneumococcal disease (PD) remain high. In addition, many children do not complete their PCV course on schedule. V114 is a 15-valent PCV that contains two epidemiologically important serotypes, 22F and 33F, in addition to the 13 serotypes present in PCV13, the licensed 13-valent PCV. MethodsThis phase III descriptive study evaluated safety and immunogenicity of catch-up vaccination with V114 or PCV13 in healthy children 7 months–17 years of age who were either pneumococcal vaccine-naïve or previously immunized with lower valency PCVs (NCT03885934). Overall, 606 healthy children were randomized to receive V114 (n = 303) or PCV13 (n = 303) via age-appropriate catch-up vaccination schedules in three age cohorts (7–11 months, 12–23 months, or 2–17 years). ResultsSimilar proportions of children 7–11 months and 2–17 years of age reported adverse events (AEs) in the V114 and PCV13 groups. A numerically greater proportion of children 12–23 months of age reported AEs in the V114 group (79.0%) than the PCV13 group (59.4%). The proportions of children who reported serious AEs varied between different age cohorts but were generally comparable between vaccination groups. No vaccine-related serious AEs were reported, and no deaths occurred. At 30 days after the last PCV dose, serotype-specific immunoglobulin G geometric mean concentrations were comparable between vaccination groups for the 13 shared serotypes and higher in the V114 group for 22F and 33F. ConclusionsCatch-up vaccination with V114 in healthy individuals 7 months–17 years of age was generally well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, regardless of prior pneumococcal vaccination. These results support V114 catch-up vaccination in children with incomplete or no PCV immunization per the recommended schedule.

Randomized comparator-controlled study evaluating efficacy and safety of pembrolizumab plus Bacillus Calmette-Guérin (BCG) in patients with high-risk nonmuscle-invasive bladder cancer (HR NMIBC): KEYNOTE-676 cohort B.

TPS597 Background: Cohort A of the phase 2 KEYNOTE-057 study showed that pembrolizumab monotherapy provided effective antitumor activity and acceptable safety in patients with BCG-unresponsive HR NMIBC with carcinoma in situ (CIS). Pembrolizumab in combination with BCG at earlier stages of HR NMIBC might provide benefit superior to that of BCG monotherapy. The open-label, comparator-controlled, phase 3 KEYNOTE-676 study (NCT03711032) will be conducted to investigate the efficacy and safety of pembrolizumab + BCG versus BCG monotherapy in patients with HR NMIBC. Cohort A will enroll patients with persistent or recurrent HR NMIBC after BCG induction. Cohort B is a new, randomly assigned cohort that will help evaluate pembrolizumab + BCG in BCG treatment–naive patients who either never received BCG treatment or received BCG treatment > 2 years before enrollment. Methods: Cohort B of KEYNOTE-676 will enroll approximately 975 patients with blinded independent central review (BICR)–confirmed HR NMIBC (T1, high-grade Ta CIS) and Eastern Cooperative Oncology Group performance status score 0-2 who underwent cystoscopy/transurethral resection of bladder tumor ≤12 weeks before randomization and had not received BCG within the past 2 years. Patients will be randomly assigned 1:1:1 to receive pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) + BCG reduced maintenance (≤6 months), pembrolizumab 400 mg IV Q6W + BCG full maintenance (≤18 months), or BCG monotherapy (BCG full maintenance). Stratification factors include NMIBC stage (CIS or no CIS) and PD-L1 expression (combined positive score [CPS] ≥10 or CPS < 10), determined by central laboratory. Disease status will be assessed by use of cystoscopy, urine cytology, and biopsy (as applicable) every 12 weeks (Q12W) through year 2, then every 24 weeks through year 5; imaging with computed tomography urography will occur every 72 weeks. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of study treatment (90 days for serious AEs). The primary end point is event-free survival (EFS). Secondary end points include complete response rate by BICR, duration of response (DOR), 12-month DOR rate (CIS only), 24-month EFS rate, disease-specific survival, time to cystectomy, overall survival, and safety. The study is enrolling or planning to enroll at sites in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT03711032.

A Randomized, Comparator-Controlled Study of HARC for Cheek Augmentation and Correction of Midface Contour Deficiencies.

HARC is a soft and flexible hyaluronic acid filler containing lidocaine, manufactured using XpresHAn® technology, restoring natural-looking volume and soft contours. To evaluate safety and effectiveness of HARC for cheek augmentation and correction of midface contour deficiencies compared to a control product HAJV (hereafter referred to as Control). Primary objective was to demonstrate non-inferiority of HARC compared to the Control, by blinded evaluation of change from baseline in midface fullness 12 weeks after last injection, using a 4 grade midface volume scale (MMVS). Subjects over the age of 21 with loss of fullness in the midface area (MMVS score 2, 3, or 4) were randomized 2:1 to treatment with HARC(n=142) or Control (n=68). Optional touch-up was allowed after 4 weeks. Study assessments included MMVS, aesthetic improvement, subject satisfaction, and safety. Subjects were followed for 48 weeks. Overall, most subjects were female (89%) and mean age was 53 years (range 24-80). Total mean volume injected was 4.3 mL for HARC and 4.9 mL for Control. Primary objective was met; mean change from baseline in MMVS score at week 12: -1.4 (HARC), -1.3 (Control), 95% CI: -0.22, 0.06. HARC effectiveness was supported by a high degree of aesthetic improvement and subject satisfaction throughout 48 weeks. Related adverse events were generally mild and transient.  HARC was well tolerated and non-inferior to Control for correction of midface fullness at 12 weeks after last injection. Aesthetic improvement and subject satisfaction were high and lasted through week 48.  J Drugs Dermatol. 2021;20(9):949-956. doi:10.36849/JDD.6191.

Efficacy of Alcaftadine 0.25% (AGN-229666) for Once-daily Prevention of Cedar-Pollen Allergic Conjunctivitis: A Phase 3 Randomized Study

ABSTRACT Purpose: This study evaluated the efficacy and safety of once-daily Alcaftadine 0.25% (AGN-229666) for prevention of signs and symptoms of Japanese cedar-pollen allergic conjunctivitis. Methods: This was a single-center, placebo-, and comparator-controlled study using the Ora-CAC® model of allergic conjunctivitis. The primary endpoint was ocular itching 16 hours after Alcaftadine 0.25% instillation; efficacy at 16 hours was compared with 0.1% Olopatadine, 4 hours after instillation. Secondary endpoints included conjunctival hyperemia. Results: 263 Japanese subjects were enrolled; 224 completed the trial. Alcaftadine 0.25% was statistically superior to vehicle for relief of ocular itching at 16 hours (p < .0001). Alcaftadine 0.25% at 16 hours was non-inferior to Olopatadine at 4 hours. Alcaftadine 0.25% was significantly better than vehicle for relief of conjunctival hyperemia. All treatments showed a low frequency of ocular adverse events. Conclusion: Once-daily Alcaftadine 0.25% is safe and effective in preventing signs and symptoms of Japanese cedar-pollen allergic conjunctivitis.

227-OR: The Effect of Dietary Fiber in Combination with Metformin Therapy in Type 2 Diabetes

Background: The efficacy of increasing dietary fiber intake (DFI) to ameliorate glycemic control in patients with type 2 diabetes (T2D) is still controversial. In this randomized open-label comparator-controlled study we tested the effect of high-fiber diet and fiber supplement on glycemic control in patients with T2D on metformin monotherapy. Methods: Seventy-eight T2D overweight patients on metformin monotherapy were randomized 1:2:1 to 12 weeks intensive nutrition program to follow high-fiber diet (HFD), dietary fiber supplementation (FS) or standard diet recommendations (SDR). Dietary recommendations were reinforced in all groups every 4 weeks by study dieticians. Biochemistry, anthropometric measures, food frequency questionnaires to asses DFI were collected at baseline and after 12 weeks. Results: At baseline groups did not differ in terms of mean age, BMI, metformin intake, HbA1c, fiber and calorie intake (p&amp;gt;0.05 for all). After three months, DFI significantly increase in both HDF and FS group but not in SDR group (HFD: 19.8 ± 6.1 g vs. 24.3 ± 6.8 g, p= 0.0001; FS: 17.5 ± 5.9 g vs. 27.0 ± 6.2 g p&amp;lt; 0.0001; SDR: 22.8 ± 9.1 g vs. 21.2 ± 6.4 g, p= 0.32). HbA1c significantly improved in all groups (HFD: 7.1 ± 0.5 % vs. 6.6 ± 0.6 %, p&amp;lt; 0.0001; FS: 7.1 ± 0.5 % vs. 6.8 ± 0.5 % p&amp;lt; 0.001; SDR: 7.2 ± 0.4 % vs. 6.7 ± 0.5 g, p&amp;lt; 0.001). All HFD, FS and SDR intervention reduced mean body weight by 2.1 ± 2.6 Kg (p&amp;lt; 0.0001), 1.0 ± 1.8 Kg (p&amp;lt; 0.05) and 1.1 ± 2.1 Kg (p&amp;lt; 0.05), respectively. Changes in HbA1c and body weight did not differ among groups. A significant correlation between calorie intake and the reduction of HbA1c levels was seen across groups (r= 0.307 p&amp;lt;0.01). No significant correlation between DFI and HbA1c levels was observed. Conclusions: Intensive nutrition education programs with monthly meetings similarly reduced HbA1c in all groups. Furthermore, our study suggested that rather than fiber intake, caloric restriction followed by moderate weight loss is the main driver for glycemic improvement in overweight patients with T2D. Disclosure F. Tramontana: None. E. Maddaloni: Consultant; Self; Merck KGaA. Speaker’s Bureau; Self; Abbott, AstraZeneca, Pikdare. S. Greci: None. G. Defeudis: None. R. Strollo: None. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. N. Napoli: None.

Comparing LigasureTM Exact dissector with other energy devices in total thyroidectomy: a pilot study.

Hemostasis is fundamental in thyroid surgery. The aim of this randomized active comparator-controlled study was to compare the effectiveness of LigasureTM Exact to previously existing sealing devices in patients undergoing thyroidectomy. A total of 180 patients were randomly allocated into 4 groups according to the hemostatic device used: Focus Harmonic Scalpel® (FHS), LigasureTM Small Jaw (LSJ), Thunderbeat® (TB), and LigasureTM Exact (LE). We recorded epidemiologic and biochemical data, operative difficulty, postoperative vocal alteration and pain, complications, operating time, grams of gland excised per minute, and hospitalization. Differences (P<0.001) were observed concerning duration of surgery, operative difficulty and quantity of gland removed per minute. Concerning duration of surgery it is shorter for LE followed by TB and then by both FHS and LSJ. Concerning the quantity of thyroid removed per minute LE leads, followed by FHS and TB. The least amount of gland removed per minute is by LSJ. Finally, operative difficulty was less for LE, while it was equal for all other three devices. Energy devices are now frequently used in thyroidectomy. Comparing these devices seems to qualify them as equal concerning post-operative complications, hemostasis, and acute inflammatory reaction. However, LigasureTM Exact Dissector seems to have better results concerning duration of surgery, quantity of thyroid tissue removed per minute and intraoperative difficulty.

The effects of erythromycin towards the treatment of persistent rhinosinusitis after functional endoscopic sinus surgery: A randomized, active comparator-controlled study.

Long-term, low-dose macrolide treatment has been in recent use to treat chronic rhinosinusitis. In this study, we investigated the effect of long-term, low-dose erythromycin on patients who had persistent rhinosinusitis after functional endoscopic sinus surgery (FESS). Patients with persistent rhinosinusitis for 3 months after FESS were recruited and randomly assigned to two groups. Patients in the erythromycin group took erythromycin (250 mg twice a day) for 12 weeks, while those in the intranasal steroid group were administered with mometasone furoate nasal spray for 12 weeks. Both before and after treatment, sino-nasal symptoms were assessed via questionnaires. Patients also received an endoscopic examination, acoustic rhinometry, smell test, and saccharine transit test. A bacterial culture was obtained from the middle meatus. Seventy-two patients completed the study, with 35 in the erythromycin group and 37 in the intranasal steroid group. Endoscopic scores decreased significantly after treatment in both groups. Erythromycin improved the smell threshold and saccharine transit time better than the intranasal steroid. In contrast, the intranasal steroid increased the second minimal cross-sectional area of the nasal cavity at a level greater than erythromycin had. Our study showed that long-term, low-dose erythromycin treatment improved the endoscopic score, smell threshold, and saccharine transit time in patients with persistent rhinosinusitis after FESS.

The Magnesium-Rich Formula for Functional Constipation in Infants: a Randomized Comparator-Controlled Study.

PurposeTo compare the effectiveness of the magnesium (Mg)-enriched formula vs. control formula in constipated infants.MethodsAn open-label, interventional, and the comparator-controlled study was conducted to evaluate the effectiveness of the Mg-enriched formula in formula-fed infants ≤6 months old presenting with functional constipation according to modified Rome IV criteria. Infants were randomized 1:1 to intervention or control formula for 30 days. Parents recorded stool consistency (hard, normal, or watery) and frequency on days 1–7 and 23–29. Physicians recorded patient baseline characteristics and performed the clinical examination at the time of three patient visits (baseline, day 8, and 30).ResultsOf the 286 recruited infants, 143 received the Mg-rich formula and 142 received the control formula. After 7 days, significantly more infants had stools with normal consistency with the Mg-rich formula compared to the infants fed with the control formula (81.8% vs. 41.1%; p<0.001). The number of infants passing one or more stools per day was increased at day 7 in the Mg-rich formula group (86.7% vs. 68.2%; p<0.001). At days 7 and 29, >25% of infants responded completely to the Mg-rich formula compared to <5% of infants fed with the control formula (p<0.001). Parents of infants in the Mg-rich formula group were very satisfied with the treatment (80.8% vs. 10.2%), with the majority willing to continue treatment after 30 days (97.9% vs. 52.6%; p<0.001).ConclusionThe Mg-rich formula significantly improved stool consistency and frequency compared to the control formula in constipated infants.

Rationale and design of ASTEROID 2, a randomized, placebo- and active comparator-controlled study to assess the efficacy and safety of vilaprisan in patients with uterine fibroids

BackgroundUterine fibroids (UFs) may be treated with progesterone receptor modulators (PRMs), which have been shown to reduce heavy menstrual bleeding and the size of UFs. To date, one PRM (ulipristal acetate) has received regulatory approval for the treatment of UFs; therapy comprises intermittent treatment courses of up to 3months each, followed by a break to allow two menstruations to occur. We report the design of ASTEROID (Assess Safety and efficacy of vilaprisan in patients with uTERine fibrOIDs) 2, a phase 2 study examining the efficacy and safety of a novel PRM, vilaprisan, in women with UFs. Methods/designIn this randomized multi-arm study, vilaprisan (2mg daily) will be administered in different regimens: continuous treatment for 12 or 24weeks, or two 12-week treatment periods separated by a break to allow one menstruation to occur. Efficacy and safety will be compared with that of ulipristal acetate (5mg daily) and placebo. Patients randomized to receive placebo for 12weeks will also be given active treatment for 12weeks. The primary measure of efficacy will be amenorrhoea rate; secondary measures include time to normalized menstrual bleeding and percentage change in UF volume. Endometrial changes will be monitored throughout the study. DiscussionThe placebo- and active comparator-controlled trial ASTEROID 2 is the first study to evaluate systematically the efficacy and safety of different treatment regimens of PRMs in women with UFs. The findings of this study will direct the planning of future clinical trials of vilaprisan.

Effects of non-pharmacological treatment of substance use in Medicare elderly with prostate cancer

or intravenous route, but the relationship between these studies and effects on abuse has yet to be confirmed. The preferred design of these studies is a randomized, double-blind, placeboand positive comparator-controlled crossover study. However, several methodological challenges arise when evaluating the AD properties of these products for the intranasal route of administration. For example, some AD products have a much larger weight and/or volumeormay, upon crushing, result in a powder of a different particle size distribution than the positive control used in the study. Because of these differences, a large sequence effect and period by treatment interaction may be observed. Some pros and cons of the current accepted designs for intranasal studies will be discussed, and a modified Williams square design will be proposed. Conclusions: To addressmethodological challengeswhen evaluating the intranasal deterrent properties of AD opioid products in human abuse potential studies a modified Williams square design is proposed. Theproposeddesigndoesnot requireweightmatching across treatments and allows for the evaluation of whether weight itself is an abuse-deterrent factor in a proposed abuse-deterrent product. Financial support: N/A.

Double-blind, placebo and active comparator-controlled study in Healthy Males followed by an open-label study in Healty Males and Females, to asses the safety, Pharmacokinetics and –dynamics of 2B3-201

Double-blind, placebo and active comparator-controlled study in Healthy Males followed by an open-label study in Healty Males and Females, to asses the safety, Pharmacokinetics and –dynamics of 2B3-201

English

The latest published Linezolid in the treatment of subjects with nosocomial pneumonia proven to be due to methicillin-resistant Staphylococcus aureus (ZEPhyR) trial was a phase IV, randomized, double-blind, multicenter, comparator-controlled study comparing the efficacy of fixed-dose linezolid to dose-optimized vancomycin in hospitalized adults for the treatment of methicillin-resistant S. aureus (MRSA) nosocomial pneumonia. They found out that the superiority of linezolid over vancomycin was with regard to both clinical responses and microbiological outcomes but without a survival advantage. However, the study had a number of shortcomings: failing to implement the guideline about vancomycin doing and goal trough level, recruitment of health care-associated pneumonia (HCAP) population, failing to explain mortality rate in different minimal inhibitory concentration (MIC) subgroups and glomerular filtration rates (GFR) subgroups etc. Limitations of the study made us consider routine use of linezolid for the treatment of MRSA pneumonia with prudence. Key words: Nosocomial pneumonia (NP), trough level, ventilator-associated pneumonia (VAP), health care-associated pneumonia (HCAP), methicillin-resistant S. aureus (MRSA).

One-year randomized study of the endometrial safety and bleeding pattern of 0.25 mg drospirenone/0.5 mg 17β-estradiol in postmenopausal women

Objectives To investigate the long-term endometrial safety and bleeding pattern of the 0.25 mg drospirenone/0.5 mg 17β-estradiol (DRSP/E2) dose combination compared with 0.5 mg norethisterone acetate (NETA)/1.0 mg E2, in postmenopausal women.Methods A total of 662 postmenopausal women aged between 40 and 65 years with an indication for hormone therapy verified by the investigator were randomized to participate in this 1-year, double-blind, active comparator-controlled study. The primary efficacy variable was the proportion of women with an endometrial biopsy assessment of ‘hyperplasia or worse’ at any time during or after 13 cycles of treatment.Results No evaluable women in the DRSP/E2 or NETA/E2 groups had an endometrial biopsy result of ‘hyperplasia or worse’. The incidence of amenorrhea was higher in the DRSP/E2 group than the NETA/E2 group during months 1–3 (69.0% vs. 56.0%), with comparable amenorrhea rates of approximately 80% during months 10–12. Improvements in menopausal symptoms (exploratory efficacy variables) were similar in the two groups, while there were fewer women with treatment-related adverse events (18.4% vs. 25.6%) or adverse events leading to discontinuation of study drug (8.4% vs. 15.1%) in the DRSP/E2 group than the NETA/E2 group. There were no treatment-related thromboembolic or cardiovascular events in the DRSP/E2 group vs. two events in the NETA/E2 group.Conclusions The low-dose, 0.25 mg DRSP/0.5 mg E2 dose combination met the criteria for endometrial safety and demonstrated a favorable risk/benefit profile in this 1-year, double-blind, randomized study of postmenopausal women.

A multicenter, randomized, double-blind clinical trial of combination therapy with Anbainuo, a novel recombinant human TNFRII:Fc fusion protein, plus methotrexate versus methotrexate alone or Anbainuo alone in Chinese patients with moderate to severe rheumatoid arthritis

This study aims to evaluate the clinical and radiological efficacy as well as safety profiles of Anbainuo, a recombinant human TNFRII:Fc fusion protein, combined with methotrexate (MTX) versus MTX alone or Anbainuo alone in the treatment of Chinese patients with moderate to severe rheumatoid arthritis (RA). In this 24-week, multicenter, double-blind, active comparator-controlled study, 396 RA patients were randomized into combination therapy group (Anbainuo plus MTX), Anbainuo group, or MTX group. Clinical response was assessed using the American College of Rheumatology (ACR)-N, ACR20, ACR50, ACR70, and van der Heijde modification of Sharp score, among which ACR-N and ACR20 were defined as primary major endpoints. After 24weeks of treatment, the ACR-N in the combination therapy group (12.79 ± 9.24%) was significantly higher than that in Anbainuo group (9.56 ± 11.16%) and in MTX group (5.08 ± 11.1%) (p = 0.00 and p = 0.00, respectively). Patients in Anbainuo group had significantly higher ACR-N than those in MTX group (p = 0.02). More patients in the combination therapy group (53.6%) achieved ACR50 improvement response than those in the MTX group (30.8%). ACR70 of combination therapy group (27.7%) was significantly higher than that of Anbainuo group (15.8%) and MTX group (7.70%), with no significant difference between Anbainuo group and MTX group. DAS28-ESR in the combination therapy group was significantly reduced compared to either monotherapy groups. Moreover, DAS28-ESR was significantly lower in Anbainou group than in MTX group. The combination therapy group also showed significantly less radiographic progression than the MTX group (p = 0.03). The total adverse events (AE) in the combination group (40.9%) was significantly higher than those in the MTX group (28.8%) (p < 0.05). Anbainuo combined with MTX therapy can effectively control the disease activity and radiographic progression of RA, while the incidence of AE also increased compared to either Anbainuo or MTX.

An exploratory study of combination buspirone and melatonin SR in Major Depressive Disorder (MDD): A possible role for neurogenesis in drug discovery

We used in vitro neurogenesis-based human neural stem cell (hNSCs) assays and rodent in vivo behavioral assays to identify potential novel antidepressants. A combination of buspirone and melatonin displayed antidepressant activity in these assays whereas neither buspirone nor melatonin alone showed any antidepressant-like profile. After evaluating numerous combination ratios, we determined that low dose buspirone 15 mg combined with melatonin-SR 3 mg yielded optimal antidepressant efficacy in our pre-clinical platform. The low dose of buspirone suggested that antidepressant efficacy might be achieved with only minimal adverse event liability. Based on these data, we conducted an exploratory 6-week, multi-center, double-blind, randomized, placebo- and comparator-controlled study of the combination of buspirone and melatonin in subjects with acute Major Depressive Disorder (MDD). The combination treatment revealed a significant antidepressant response in subjects with MDD on several measures (Clinical Global Impression of Severity and Improvement, Inventory of Depressive Symptomatology) compared to either placebo or buspirone 15 mg monotherapy. These preliminary findings have clinical implications and suggest that a platform of pre-clinical neurogenesis matched with confirmatory behavioral assays may be useful as a drug discovery strategy.

Immunogenicity and safety of a single intramuscular dose of a diphtheria–tetanus toxoid (Td) vaccine (GC1107) in Korean adults

The current study aimed to evaluate immunogenicity and safety of a newly developed diphtheria–tetanus toxoid (Td) vaccine, GC1107 (Green Cross Corporation, Yongin, Korea), in comparison with placebo and active comparator (licensed Td vaccine) in healthy Korean adults. A randomized, double-blind, placebo and active comparator-controlled study was conducted. Forty subjects were randomly administered a single intramuscular dose of GC1107, active comparator or placebo in a ratio of 2:1:1. At 2 and 4 weeks after vaccination, anti-diphtheria antibody levels in the GC1107 group increased 9.2 and 9.3 times, respectively, compared to predose titers. The corresponding values were 9.3 and 8.3 times for the active comparator group. Anti-tetanus antibody levels increased 39.0 and 37.9 fold at 2 and 4 weeks, respectively, after GC1107 administration, and 12.2 and 14.7 fold after active comparator administration. No increases in tetanus or diphtheria antibody were observed for the placebo group. Adverse events in the GC1107 and active comparator groups were more frequent than for the placebo group, but there were no significant differences between the two active treatments. In conclusion, GC1107 was well tolerated and provided significant boosts of anti-tetanus and anti-diphtheria antibodies.