Oral Combination Therapy Research Articles

AB0786 HUGHES–STOVIN SYNDROME: A PECULIAR AUTOIMMUNE ORIGIN OF PULMONARY ANEURYSMS

Background:Hughes-Stovin Syndrome (HSS) is a rare potentially fatal vasculitis supposedly belonging to the spectrum of Behçet disease without ocular involvement. HSS tends to play by a temporal pattern, starting with thrombosis and followed by formation of pulmonary aneurysms. Since its mortality can reach 25% of cases, the early recognition and the appropriate therapy represent the major challenges.Objectives:In this report, we aimed at describing a rare case of HSS successfully treated in accordance with a prompt combined management with endovascular approach and immunosuppressive treatments.Methods:We described a Caucasian 33-year-old man presented to the Emergency Room of our Hospital with hemoptysis associated with dyspnea and chest pain, without fever and hypotension, with a 2-year history of painful genital and oral ulcers. Blood test revealed anemia, elevated white cell count with increased C-reactive protein (77 mg/L) and D-dimer (2740 ng/mL). Doppler ultrasonography of legs showed thrombosis of the left femoral vein, while CT-angiography reported multiple aneurysms of the pulmonary arteries. An early and extensive work-up for infections and autoimmunity did not document relevant abnormalities. An appropriate genetic assessment revealed the HLA-B51 positivity. The patient immediately underwent endovascular embolization with coils and plugs of the largest pulmonary aneurysm, and inferior vena cava filter placement. Then, he started methylprednisolone (1 mg/kg/day) IV for three days in association with LMWH (6000 IU/day). Prednisone (1 mg/kg/day) in combination with cyclophosphamide (100 mg daily) were started orally, with tapering of steroids within a month. At the tight follow up (1 month and 3 months later), no genital and oral ulcers nor vascular thrombosis occurred, and acute phase reactants were in normal range. The 3-month-CT angiography showed a complete resolution of the aneurysms and no new changes.Results:The peculiar diagnosis of HLAB51 positive HSS with multiple pulmonary aneurysms was made. The appropriate imaging followed by a prompt endovascular embolization of aneurysms with LMWH treatment were successfully performed. Interestingly, the oral combination therapy with corticosteroid and cyclophosphamide showed a rapid efficacy with a relevant safety profile. At the tight follow up, the young man improved significantly with clinical signs and pulmonary changes (Figure 1 next page).Conclusion:This case is of interest because of the early recognition of such a rare disease that allowed an adequate combined radiological, vascular, and rheumatologic approach. In our case, LMWH resulted useful in preventing the pulmonary embolism, despite the use of anticoagulants is still debated in HSS. Moreover, the endovascular embolization let a less invasive approach to surgery without the need for multiple surgical procedures. For the first time, we documented that oral cyclophosphamide showed an early efficacy as a first line therapy of a HLA-B51 HSS.

11-oxyandrogen Concentrations in Adolescents With Polycystic Ovary Syndrome (PCOS)

Abstract PCOS is common in adolescents and includes excess testosterone concentrations. The clinical importance of 11-oxyandrogens in PCOS is unclear. We sought to determine if fasted morning 11-oxyandrogens: 1) better identify PCOS diagnosis compared to testosterone, 2) relate to clinical comorbidities of PCOS, 3) are altered with combined oral contraceptive pill (COCP) or metformin therapy. Data from 186 adolescent females aged 12-21 years, mostly obese, enrolled in one of 6 studies in our division were included: 115 untreated PCOS (13 lean, BMI 22.5±2.2 kg/m2; 102 overweight/obese, BMI 35.4±5.3), 9 obese PCOS treated with COCP (BMI 33.7±5.7), 6 obese PCOS treated with metformin (BMI 36.4±5.3) and 70 normally cycling controls (19 lean, BMI 19.9±1.4; 52 overweight/obese BMI 35.5±10.4). Three 11-oxyandrogens (11-hydroxyandrostenedione (11OHA), 11-hydroxytestosterone (11OHT), and 11-ketotestosterone (11KT) and total testosterone were analyzed via liquid chromatography tandem mass spectroscopy (LabCorp/Esoterix, Calabasas, CA). Data between 1) untreated PCOS and controls and 2) untreated PCOS and the 2 treatment groups were compared. ROC analysis was performed to evaluate accuracy of diagnosis of PCOS and Pearson’s correlation coefficient was calculated for 11-oxyandrogens and clinical measures. Untreated PCOS girls had higher 11OHA (129±77 ng/dL PCOS vs 97±52 control, p=0.003) and 11OHT (13.8±7.9 ng/dL PCOS vs 10.5±6.7 control, p=0.005) compared to controls, with no difference in 11KT (30.7±17.3 ng/dL PCOS vs 26.6±16.6 control, p=0.208). Only 11OHA remained significant after controlling for obesity via multiple linear regression. However, neither of these metabolites better predicted PCOS status compared to testosterone (ROC analysis: 11OHA AUC=0.620, p=0.006; 11OHT AUC=0.638, p=0.002; total testosterone AUC=0.840, p<0.001, free androgen index AUC 0.860, p<0.001). Among girls with PCOS, all three 11-oxyandrogens correlated with hirsutism severity as graded by Ferriman Gallwey score. COCP treatment decreased 11KT concentrations compared to untreated PCOS (32±17 untreated vs 17±8 ng/dL COCP; p=0.039) as well as total testosterone (46.9±21 untreated vs 28.1±12.9 ng/dL COCP; p<0.006). However, metformin treatment had no effect 11-oxyandrogens, although total testosterone was lower (46.9±21 untreated vs 26.5±5.9 metformin; p=0.01). Whereas 11-oxyandrogens would not aid in the diagnosis of PCOS, they relate to excess hair growth and 11KT decreases with COCP therapy. Further work is needed to determine the relationship with metabolic outcomes and the clinical utility of measuring these androgens in PCOS.

Combination of topical and oral glutathione as a skin-whitening agent: a double-blind randomized controlled clinical trial.

The antimelanogenesis effect of topical and oral glutathione has been shown in several in vitro and clinical studies. However, whether combination of topical and oral glutathione is superior to topical or oral monotherapy is unknown. This study aimed to compare the skin-whitening effect of topical and oral glutathione combination therapy against topical and oral monotherapy. This double-blind randomized controlled study was done on 46 participants who were divided into two equal groups. Each group received oral placebo and oral glutathione, respectively. All participants were also instructed to apply topical placebo and glutathione to each facial side, respectively. Colorimeter examination was done biweekly using mexameter and chromameter for 8weeks. One-way ANOVA test was used to compare the results of all groups. The combination group showed significantly lower melanin index (MI) and L* score to placebo (P<0.05). The mean MI and L* score of the combination group were the highest of all groups. Statistical significance of difference in L* score was reached when the combination group was compared to the oral placebo and topical glutathione group (P<0.05). This study showed that topical and oral glutathione were effective skin-lightening agents. Furthermore, combination of topical and oral glutathione might be superior to monotherapy.

Development of Bilayer Tablet Containing Saxagliptin Immediate Release and Metformin Sustained Release Using Quality by Design Approach

Objective: Adequate glycemic control in diabetes patients requires oral combination therapy. Saxagliptin is a dipeptidyl peptidase-4 inhibitor having fewer adverse effects, and metformin is the first-line medicine for diabetes treatment. The aim of this research work is to develop a bilayer tablet of saxagliptin and metformin in fixed-dose combination (FDC) using quality by design (QbD) to acquire the immediate release of saxagliptin and sustained release of metformin from bilayer tablet to ultimately achieve superior patient compliance. Methods: The development of the bilayer tablet was done in four stages using QbD. In the first step, quality target product profile (QTPP) of bilayer tablet was defined, and critical quality attributes (CQAs) were identified by risk estimation matrix and taguchi design; an immediate release saxagliptin layer was optimized in the second step, optimization of sustained-release metformin layer was carried out in the third step, and in the final step, bilayer tablet was prepared and characterized. The effect of independent parameters, i.e., magnesium stearate level (X1), kneading time (X2) and lubrication time (X3) on Carr’s Index (Y1), percentage relative standard deviation of content uniformity (Y2) and drug release at 30 minutes (Y3), were estimated for optimization of immediate release saxagliptin layer using Box-Behnken design (BBD). The effect of independent parameters, i.e., hydroxypropyl methylcellulose level (X4), compritol level (X5) and magnesium stearate level (X6) on Carr’s Index (Y4), drug release at 2 h (Y5), drug release at 5 h (Y6) and drug release at 10 h (Y7) were estimated for optimization of sustained-release metformin layer using BBD. Results: The optimized composition of immediate release saxagliptin layer estimated using numerical optimization by Design expert was 0.88% (X1), 15 minutes (X2) and 3.85 minutes (X3) with predicted variables, i.e., 10.59% (Y1), 3.16% (Y2) and 85% (Y3). The optimized composition of sustained- release saxagliptin layer predicted through numerical optimization was 30% (X4), 3.36% (X5) and 0.9% (X6) having 10.89% (Y4), 43.44% (Y5), 60% (Y6) and 85.14% (Y7). In-vitro dissolution study of bilayer tablet showed immediate release of Saxagliptin (approximately 85% in 30 minutes) and sustained release of metformin illustrating 43.21±1.21, 60.86±2.96 and 86.26±1.38% drug release at 2, 5 and 10 h, respectively. The release exponent for the Korsmeyer-Peppas model for Saxagliptin and metformin was 0.237 (&lt;0.45) and 1.536 (n&gt;0.85), indicating Fickian and super case II transport drug release behavior, respectively. Conclusion: By QbD approach, bilayer tablet containing saxagliptin and metformin was successfully developed, and influence of various formulation parameters on CQAs of drug products was understood with fewer experiments. This leads to the conclusion that cost can be reduced using QbD in the development of FDC for improving patient compliance.

Oral maintenance therapy using apatinib combined with S-1/capecitabine for esophageal squamous cell carcinoma with residual disease after definitive chemoradiotherapy.

Background: A substantial number of patients with esophageal squamous cell carcinoma (ESCC) do not achieve complete remission after definitive concurrent chemoradiotherapy (dCRT). We performed this retrospective study to evaluate the efficacy and safety of apatinib combined with S-1/capecitabine as the oral maintenance therapy for these patients.Methods: Thirty-nine ESCC patients with residual disease after dCRT were included. Patients were treated with apatinib combined with S-1 /capecitabine after dCRT. Efficacy, toxicity, and survival were analyzed.Results: Of the 39 patients, 5 (12.8%) achieved a partial response and 29 (74.4%) achieved stable disease, yielding a disease control rate of 87.2%. The median progression-free survival (PFS) and overall survival (OS) were 27.5 (95%CI: 14.9 - 40.1) and 38.1 (95%CI: 31.3 - 44.8) months. Most frequent adverse events were of grade 1 to 2. Multivariate analysis revealed the occurrence of any adverse events (HR = 0.274, 95%[CI] = 0.119 - 0.630) correlated to better PFS and occurrence of proteinuria (HR = 0.108, 95%[CI] = 0.025 - 0.456) predicted better OS.Conclusion: The oral combination therapy consisting of apatinib and S-1/capecitabine showed a tolerable toxicity profile and achieved satisfactory disease control in ESCC patients with residual disease after dCRT.

From Health-Related Quality of Life (HRQoL) of Patients with Pulmonary Hypertension to Patient Experience with the Care Received: Should We Be More Aware of Current Patient Needs?

Self-perceived health-related quality of life (HRQoL) of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and their experience with the care received are important for improving their management. We conducted a study to assess both patient-reported outcomes (PROs) and how they interrelate. This was a cross-sectional, observational study of consecutive patients with PAH and CTEPH attending pulmonary hypertension (PH)-specialized units at 25 hospitals in Spain. PRO measurements used included CAMPHOR/EQ-5D-5L questionnaires (HRQoL) and IEXPAC (healthcare experience). Patient characteristics were collected. Relationships were analysed with Pearson's correlation coefficient and linear regression analyses. A total of 185 patients with PAH and 93 patients with CTEPH aged 54.4 ± 14.4 and 64.8 ± 13.4years were included: 63.6% and 72% were functional class (FC) I-II; median time from diagnosis was 3 and 2years, respectively. Most patients with PAH received combination oral therapy. CAMPHOR scores indicated moderate-to-high impairment in the "activity" scale (PAH 21.6 ± 6.8; CTEPH 21.0 ± 6.3). EQ-5D-5L index and visual analogue scale (VAS) score (PAH 0.59 ± 0.15 and 65.55 ± 21.54; CTEPH 0.59 ± 0.13 and 66.95 ± 18.71, respectively) indicated moderate HRQoL impairment. HRQoL was mostly affected by FC. IEXPAC scores (PAH 7.08 ± 1.56 and CTEPH 7.13 ± 1.61) indicated good healthcare experience. In patients with PAH, the CAMPHOR "symptom" and "QoL" domains inversely correlated with the IEXPAC "patient self-management" factor. In patients with long-standing PAH and CTEPH with good disease control, functional limitations greatly impact HRQoL while symptoms and generic QoL were less affected. Healthcare received was perceived as good; however, use of information and communication technologies, patient associations and promotion of self-management should improve for enhanced patient experience.

Abstract PS10-45: Budget impact of introducing neratinib for third-line treatment of HER2+ metastatic breast cancer in the United States

Abstract Background Neratinib, an oral, irreversible tyrosine kinase inhibitor of multiple HER receptors, was recently approved in combination with capecitabine (neratinib doublet regimen) in the United States (US) for adults with HER2+ metastatic breast cancer (mBC) who have received 2 or more anti-HER2 therapies. Clinical trials showed that neratinib plus capecitabine significantly improved progression-free survival versus lapatinib plus capecitabine. There are several existing and potential treatment options for this population with varying efficacies, side effect profiles, and costs. Objective This analysis estimates the budget impact for US health care payers of adding a neratinib doublet regimen to the currently available third-line HER2+ mBC treatments in the US. Methods A budget-impact model was developed to compare health care payer costs associated with third-line treatment of HER2+ mBC over 5 years between a treatment setting with neratinib and a treatment setting without neratinib for a hypothetical 1-million-person commercial plan of adults over age 18. The treatment options considered in the model include neratinib doublet regimen, oral combination therapy with lapatinib and capecitabine (lapatinib doublet regimen), tucatinib plus capecitabine plus trastuzumab (tucatinib triplet regimen), and intravenous fam-trastuzumab deruxtecan-nxki (DS-8201 single agent). The population eligible for treatment was calculated based on prevalence and incidence of HER2+ mBC and progression to third-line HER2-direct treatment; estimates were obtained from the published literature. The impact of including neratinib doublet regimen was assessed under two market share scenarios: one in which all regimens had equal market share and a second in which a clinical expert provided judgement on projected uptake of the regimens over the five-year period. In the treatment setting without the neratinib regimen, market shares for neratinib were distributed equally to the other treatments. Treatment duration, dosing, adverse event incidence, and monitoring requirements were obtained from key clinical trials and prescribing information. Drug acquisition costs, unit monitoring costs, and adverse event costs were obtained from wholesale acquisition costs, fee schedules, and the Healthcare Cost and Utilization Project, respectively. The total incremental costs and per-member-per-month (PMPM) costs were calculated by comparing total health plan costs in the treatment setting with neratinib with costs in the treatment setting without neratinib over a 5-year period. Costs were presented in 2019 US dollars. Results It was estimated that 47 patients would be eligible for third-line HER2 mBC treatment in the first year, with an additional 17 incident patients becoming eligible each subsequent year. Average monthly costs per treated patient were $15,037, $9,283, $27,759, and $14,826 for neratinib doublet regimen, lapatinib doublet regimen, tucatinib triplet regimen, and DS-8201, respectively. When market shares were assumed to be even across regimens, the treatment setting with neratinib doublet regimen reduced total annual health plan costs by $1.4 million ($0.02 PMPM) over 5 years compared with the treatment setting without neratinib doublet regimen. Cost reductions for the treatment setting with neratinib doublet regimen were $575,738 ($0.01 PMPM) over 5 years when market shares were based on clinical expert estimates. Conclusions The introduction of neratinib over the course of 5 years has the potential to reduce US health plan costs for the treatment of patients with HER2+ mBC by reducing the usage of more expensive treatment regimens. Citation Format: Seri AL Anderson, Justin Carrico, Thor-Henrik Brodtkorb, Deepa Lalla, Adam Brufsky. Budget impact of introducing neratinib for third-line treatment of HER2+ metastatic breast cancer in the United States [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-45.

Results of a clinical trial of the efficacy and safety of vildagliptin and metformin fixed combination in real clinical practice in Russia (MASTER study)

BACKGRAUND: The widespread prevalence of type 2 diabetes mellitus (T2DM), high mortality and disability of such patients are the reason for the constant active search for effective approaches to hypoglycemic therapy. Recent years have been marked by a change in the strategy for treatment initiation of T2DM. In clinical studies, evidence has been obtained about the benefits of prescribing combination therapy from the time of diagnosis. It seems important to study this treatment option also in real clinical practice.AIMS: To evaluate the effectiveness and safety of the initiation with Galvus Met® as compared with any other combination therapy approaches used in everyday clinical practice.MATERIALS AND METHODS: multicenter prospective observational study in 15 regions of Russia lasting 6 months. Patients were included in the study after the endocrinologist made a decision on the appointment of therapy. Of the men and women over 18 years of age with first diagnosed or previously untreated type 2 diabetes and a level of glycated hemoglobin &gt;7.5%, two groups were formed. The first group included patients who received vildagliptin + metformin (Galvus Met®) in a fixed dose of 50/1000 mg, n=729, the second — another double combination (with the exception of insulin and GLP-1), n=669. The primary endpoint was defined as the proportion of patients (%) who achieved the level of HbA1c &lt;7.0% without proven hypoglycemia at the end of the observation. The NHPQ questionnaire was used to assess the frequency of hypoglycemia.RESULTS: 1385 patients completed the study. For the other combination therapy group, metformin and sulfonylurea derivatives were most often selected (66.5%). In the Galvus Met® group, 68.7% of patients achieved an HbA1c level of &lt;7.0% without proven hypoglycemia, which is significantly better compared to the group of other combinations (40.7%, p &lt;0.001). Galvus Met® therapy contributed to a significantly greater decrease in HbA1c levels by the end of the study compared to other combinations (delta HbA1c -1.6 ± 0.8% versus -1.4 ± 0.9%, p &lt;0.001). In the same group, the average level of HbA1c reached 6.7 ± 0.6% by the end of the study versus 7.1 ± 0.8% in the comparison group, p &lt;0.001. In the Galvus Met® group, body weight decreased by 3.2 ± 3.9 kg, and in the comparison group by 1.3 ± 4.8 kg, p &lt;0.001. The frequency of hypoglycemia episodes in the Galvus Met® group by the end of the study was significantly lower than in the comparison group: 0.8 ± 0.7 episodes per person, versus 1.4 ± 0.8, p = 0.037. In the Galvus Met® group, there were significantly fewer adverse events (4.9% versus 17.7%, p &lt;0.001).CONCLUSIONS: In real clinical practice, Galvus Met® starting therapy has shown better efficacy and safety in terms of achieving glycemic control, HbA1c dynamics, effects on body weight, the frequency of hypoglycemic conditions compared with other combined oral hypoglycemic therapy.

Comparison of art outcome in frozen embryo transfer cycle using oral estradiol valerate and estradiol transdermal gel

Aim: Endometrial preparation with exogenous estrogen is a common practice in frozen embryo transfer (FET) cycles. The aim of this study was to compare the clinical outcome of oral estradiol valerate versus transdermal estrogen (17-β estradiol) gel in FET cycles. Materials and Methods: A prospective pilot study was carried out at a tertiary fertility clinic after Ethics Committee approval from January 2018 to December 2018. It included 103 infertile women who underwent FET cycles. Either oral estradiol valerate or transdermal 17-beta estradiol was used for endometrial preparation. Combination was used in case of breakthrough bleeding or if optimal endometrial thickness was not achieved. Baseline demographic parameters and details of the stimulation protocol and embryogenesis in fresh cycle were noted. In the FET cycle, the patient was seen on day 2 of menstrual cycle, where baseline ultrasound (USG), estradiol, and progesterone levels were done. If normal, the patients were given either oral or dermal preparation. The patient was seen again on day 9 for endometrial thickness and if required again after 2 days till endometrial thickness was 9 mm. If optimal endometrial thickness was not achieved or there was breakthrough bleeding, combination of both oral and dermal preparation was used. Once the endometrial thickness was 9 mm or more, progesterone was started, and ET was done on day 5. On the day of progesterone initiation, endometrial thickness, endometrial volume by 3D, and Doppler indices [pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV)] were noted. The primary outcome of the study was clinical pregnancy rate (CPR) and live birth rate (LBR). Results: There was no statistical difference in any of the demographic parameters in groups A and B. In group C, the pregnant patients were younger with higher body mass index and follicle-stimulating hormone and lower anti-Mullerian hormone and antral follicle count when compared with those who did not conceive. Demographics of the fresh cycle did not show any significant difference in dose and duration of stimulation, fertilization, cleavage, and blastulation rate in group A. In group B, the fertilization rate was significantly higher in the pregnant group (0.001), whereas the other parameters were similar. In group C, the pregnant group required more dose and days of stimulation and had lower oocytes retrieved but had a higher blastulation rate. In the hormone replacement therapy (HRT) cycle, there was no difference in the mean duration of HRT in groups A and B but was significantly higher in group C when compared with group A. The CPR with oral estradiol valerate, transdermal gel, and combination therapy was 34.85%, 35%, and 52.94%, respectively. The LBR with oral estradiol valerate, transdermal gel, and combination therapy was 25.76%, 30%, and 47.06%, respectively. Though the CPR and LBR were higher in group C, it did not reach statistical significance and this could be due to small sample size. There was no difference in the abortion rate (oral 7.58%, gel 5%, combination 5.88%) between the three groups. The implantation rate (oral 26%, gel 25.8%, combination 29.03%) in the three groups was also similar. There was also no statistical difference in the endometrial thickness, volume, and blood flow between the three groups. The cut-off values for Doppler indices for a positive pregnancy were as follows: Group A—PSV: >8.7, RI: <0.99, PI: >1.54; Group B—PSV: >5, RI: <0.72, PI: >2.1; Group C—PSV: >5.6, RI: <0.64, PI: >1.29. Conclusion: Both the oral estradiol valerate and transdermal 17-beta estradiol were equally effective for optimal outcome in an FET cycle in HRT. Those not responding to single preparation may benefit from combination therapy. Transdermal 17-beta estradiol gel may be of use in those patients who have breakthrough bleeding with oral preparation which may be due to hepatic bypass effect.

A Paradigm Shift in Osteonecrosis Treatment with Bisphosphonates: A 20-Year Study.

Background:Bisphosphonates are proven to be effective in obviating the need for surgical intervention in osteonecrosis of the femoral head. However, the late onset of pain relief hampers compliance. We present the clinical and radiographic outcome of a combination therapy compared with alendronate-only therapy for the management of osteonecrosis of the femoral head.Methods:The data of patients diagnosed with osteonecrosis of the femoral head from January 2001 to January 2017 were retrospectively analyzed. The first group, the alendronate treatment group, comprised 432 hips (358 patients) diagnosed from January 2001 to January 2009 and treated with 10-mg oral alendronate daily for 3 years. The second group, the combination treatment group, comprised 442 hips (386 patients) diagnosed from February 2009 to January 2017 and treated with a combination therapy of 35-mg oral alendronate twice weekly and 5-mg intravenous zoledronic acid once annually for 3 years. Clinical assessment was performed using the Harris hip score, the visual analog scale (VAS) pain score, and the clinical failure rate. Radiographic assessment was performed for progression and collapse.Results:In the alendronate treatment group, at a mean follow-up of 129.6 months (range, 60 to 220 months), 74.5% did not require a surgical procedure, and, in the combination treatment group, at a mean follow-up of 69 months (range, 37 to 105 months), 88.9% did not require a surgical procedure. The clinical failure rate at 3 years was 4% for stage I, 11% for stage II, and 29% for stage III in the alendronate treatment group, and it was 5% for stage I, 9% for stage II, and 32% for stage III in the combination treatment group. Patients in the combination treatment group had a significantly better improvement in VAS score at 6 weeks (from 7.10 to 3.66) compared with patients in the alendronate treatment group (from 7.93 to 7.00).Conclusions:Our study shows that both oral alendronate-only therapy and bisphosphonate combination therapy retard the progression of disease, reduce the rate of collapse, and, hence, reduce the need for joint replacement surgery. However, bisphosphonate combination therapy offers earlier improvement in pain and functional scores compared with oral alendronate therapy only.Level of Evidence:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Inhaled iloprost as third add‐on therapy in idiopathic pulmonary arterial hypertension

Triple combination therapy is suggested in current pulmonary arterial hypertension guidelines in case of unsatisfactory treatment with oral double combination therapy. However, there is a lack of evidence concerning some of the drug combinations currently employed. We demonstrate the clinical and hemodynamical benefits of inhaled iloprost as third add-on therapy in idiopathic pulmonary arterial hypertension.

Oral Pulse Betamethasone, Methotrexate, and Combination Therapy to Treat Severe Alopecia Areata: A Randomized, Double-blind, Placebo-controlled, Clinical Trial.

The purpose of this study is to compare oral betamethasone pulse therapy, methotrexate therapy and a combination of the two for patients with Alopecia Areata (AA) as an autoimmune disorder. In this study, 36 patients with severe AA were selected and classified into three groups of 12: 1- Oral betamethasone therapy (3 mg, once a week) with placebo; 2- Oral methotrexate (15 mg, once a week) with placebo; and 3- A combination of methotrexate (15 mg, once a week) and betamethasone (3 mg, once a week). The Severity Alopecia Tool (SALT) was used to measure improvements in the lesions through photographs, and the patients also rated their condition on the Visual Analogue Scale (VAS). Assessments were performed, and the results were compared at baseline and then at intervals of three months for nine months. The demographics and SALT score were similar in the three groups (P > 0.05). All the groups showed improvements in SALT, VAS and photographic scores three months after beginning the treatment (P < 0.001). Betamethasone therapy (P = 0.006) and combination therapy (P < 0.001) provided greater SALT improvement than methotrexate, and combination therapy led to a greater improvement in VAS and photographic findings compared to the two other groups (P < 0.05). Oral steroid, methotrexate and combination pulse therapy were effective treatments for AA, while oral steroid pulse therapy and combination therapy were superior to methotrexate.

Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.

Background:The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.Methods:Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan–Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.Results:Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12–47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.Conclusion:Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings. The reviews of this paper are available via the supplemental material section.

Selexipag for the treatment of pulmonary arterial hypertension

ABSTRACT Introduction : Pulmonary arterial hypertension (PAH) is a rare pulmonary vasculopathy. This review focuses on selexipag, a prostacyclin receptor agonist validated for the treatment of PAH. Areas covered We review the structure, mechanisms of action, pharmacokinetics, and pharmacodynamics of selexipag. Clinical efficacy and tolerability are discussed using the main clinical trial published for selexipag (GRIPHON) and its post-hoc analysis. Expert opinion Selexipag should be added as a triple oral combination therapy in case of insufficient response to oral combination therapy with endothelin receptor antagonist and phosphodiesterase 5 inhibitor. However, selexipag should not replace parenteral prostacyclin in high-risk patients.

Paediatric formulations of artemisinin-based combination therapies for treating uncomplicated malaria in children.

BackgroundIn endemic malarial areas, young children have high levels of malaria morbidity and mortality. The World Health Organization recommends oral artemisinin‐based combination therapy (ACT) for treating uncomplicated malaria. Paediatric formulations of ACT have been developed to make it easier to treat children.ObjectivesTo evaluate evidence from trials on the efficacy, safety, tolerability, and acceptability of paediatric ACT formulations compared to tablet ACT formulations for uncomplicated P falciparum malaria in children up to 14 years old.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; the Latin American and Caribbean Health Science Information database (LILACS); ISI Web of Science; Google Scholar; Scopus; and the metaRegister of Controlled Trials (mRCT) to 11 December 2019.Selection criteriaWe included randomised controlled clinical trials (RCTs) of paediatric versus non‐paediatric formulated ACT in children aged 14 years or younger with acute uncomplicated malaria.Data collection and analysisTwo authors independently assessed eligibility and risk of bias, and carried out data extraction. We analyzed the primary outcomes of efficacy, safety and tolerability of paediatric versus non‐paediatric ACT using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were: treatment failure on the last day of observation (day 42), fever clearance time, parasite clearance time, pharmacokinetics, and acceptability.Main resultsThree trials met the inclusion criteria. Two compared a paediatric dispersible tablet formulation against crushed tablets of artemether‐lumefantrine (AL) and dihydroartemisinin‐piperaquine (DHA‐PQ), and one trial assessed artemether‐lumefantrine formulated as powder for suspension compared with crushed tablets. The trials were carried out between 2006 and 2015 in sub‐Saharan Africa (Benin, Mali, Mozambique, Tanzania, Kenya, Democratic Republic of the Congo, Burkina Faso, and The Gambia).In all three trials, the paediatric and control ACT achieved polymerase chain reaction (PCR)‐adjusted treatment failure rates of < 10% on day 28 in the per‐protocol (PP) population.For the comparison of dispersible versus crushed tablets, the two trials did not detect a difference for treatment failure by day 28 (PCR‐adjusted PP population: RR 1.35, 95% CI 0.49 to 3.72; 1061 participants, 2 studies, low‐certainty evidence). Similarly, for the comparison of suspension versus crushed tablet ACT, we did not detect any difference in treatment failure at day 28 (PCR‐adjusted PP population: RR 1.64, 95% CI 0.55 to 4.87; 245 participants, 1 study).We did not detect any difference in serious adverse events for the comparison of dispersible versus crushed tablets (RR 1.05, 95% CI 0.38 to 2.88; 1197 participants, 2 studies, low‐certainty evidence), or for the comparison of suspension versus crushed tablet ACT (RR 0.74, 95% CI 0.17 to 3.26; 267 participants, 1 study).In the dispersible ACT arms, drug‐related adverse events occurred in 9% of children in the AL study and 34% of children in the DHA‐PQ study. In the control arms, drug‐related adverse events occurred in 12% of children in the AL study and in 42% of children in the DHA‐PQ study. Drug‐related adverse events were lower in the dispersible ACT arms (RR 0.78, 95% CI 0.62 to 0.99; 1197 participants, 2 studies, moderate‐certainty evidence).There was no detected difference in the rate of drug‐related adverse events for suspension ACT versus crushed tablet ACT (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study).Drug‐related vomiting appeared to be less common in the dispersible ACT arms (RR 0.75, 95% CI 0.56 to 1.01; 1197 participants, 2 studies, low‐certainty evidence) and in the suspension ACT arm (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study), but both analyses were underpowered.No study assessed acceptability.Authors' conclusionsTrials did not demonstrate a difference in efficacy between paediatric dispersible or suspension ACT when compared with the respective crushed tablet ACT for treating uncomplicated P falciparum malaria in children. However, the evidence is of low to moderate certainty due to limited power. There appeared to be fewer drug‐related adverse events with dispersible ACT compared to crushed tablet ACT. None of the included studies assessed acceptability of paediatric ACT formulation.

Long-term efficacy and safety of anti-hyperglycaemic agents in new-onset diabetes after transplant: Results from outpatient-based 1-year follow-up and a brief review of treatment options

Background and aimsEvaluation of long-term efficacy and safety of various anti-hyperglycaemic agents (AHA) for glycaemic control in NODAT, in stable kidney transplant recipients (KTRs) during 1-year outpatient follow-up. MethodsWe collected FPG, PPG, HbA1c, serum creatinine, eGFR, blood tacrolimus level, hypoglycaemia and body weight values from an existing database of KTRs diagnosed to have NODAT. Those newly initiated on AHA over 3 months post-transplant; received standard triple immunosuppressive therapy; and followed up for 1-year after referral, were included. ResultsIn ninety-five patients’ (Male = 65), mean decrease at 1-year from baseline in FPG (185.01 ± 62.11 mg/dL), PPG (293.21 ± 85.23 mg/dL) and HbA1c (8.48 ± 1.08%) was 67.09, 126.11 and 1.4 respectively (p < 0.0001). At 1-year, mean HbA1c was 7.08 ± 0.38%, ninety-one patients achieving HbA1c ≤ 7.5%. Fifty-two patients received oral combination therapy based on linagliptin/metformin/repaglinide/gliclazide, 19 received insulin-based regimen, and 24 received linagliptin monotharapey. Thirty patients reported hypoglycaemia (10 with gliclazide and 15 with insulin) and fifty patients gained body-weight at 1-year. Mean serum creatinine and eGFR significantly improved by 0.29 and 15.77 from baseline of 1.56 ± 0.62 mg/dL and 53.95 ± 16.10 mL/min/1.73 m2 respectively. ConclusionsSignificant proportion of NODAT patients achieved long-term glycemic control with improved renal function. Combination therapy was needed in most within 1-year. Linagliptin monotherapy was effective, without producing hypoglycaemia or weight gain.

Inhibiting the Nuclear Exporter XPO1 and the Antiapoptotic Factor BCL2 Is Synergistic in XPO1 Mutant and Wildtype Lymphoma

We have recently shown that XPO1 mutations are drivers of lymphomagenesis and occur across B-cell lymphomas, specifically in chronic lymphocytic leukemia (CLL), classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. The co-occurrence of other oncogenic events cooperating with XPO1 provides an opportunity for combined targeted therapy. Increased expression of the anti-apoptotic factor BCL2 has long been known to be a critical part of the pathophysiology of B-cell lymphomas. Recently, the oral BCL2 inhibitor, venetoclax, was approved in CLL and is currently being evaluated in clinical trials for other B-cell lymphomas. Selinexor is a potent, oral XPO1 inhibitor that was recently approved in multiple myeloma and diffuse large B-cell lymphoma. XPO1 inhibition exerts its antineoplastic effects by blocking key lymphomagenic pathways, such as NFκB, and decreasing the anti-apoptotic protein survivin. We therefore hypothesized that combining selinexor and venetoclax would have potential synergy and provide an oral precision combination therapy for relapsed, refractory lymphoma. We first set out to determine whether XPO1 mutant lymphoma cell lines showed differential response to either selinexor or venetoclax monotherapy. Five lymphoma cell lines; 3 diffuse large B-cell lymphoma (SU-DHL-6, SU-DHL-16, FARAGE) and 2 classical Hodgkin lymphoma (L428 and SUP-HD1), were subjected to next-generation sequencing (NGS) to assess for the presence or absence of XPO1 mutations. SUDHL-16 and SUP-HD1 were heterozygous for the XPO1 E571K hotspot mutation while SUDHL-6, FARAGE and SUP-HD1 were wildtype at the XPO1 locus. These 5 cell lines were used to assess sensitivity to Selinexor and/or Venetoclax. The CellTiter Glo assay was used to assess cell viability after 72 hours of treatment. Assays were performed in triplicate on 96-well plates that were read using a Spectramax plate reader. The XPO1 mutant cells showed increased sensitivity to selinexor (XPO1 mutant IC50 = 16-35nM; XPO1 WT IC50 = 41-231nM) as previously seen in conditional knockin mouse models of XPO1 mutant CLL (Figure A). Additionally, the XPO1 mutant cell lines showed increased sensitivity to single-agent venetoclax (XPO1 mutant IC50 = 2-13nM; XPO1 WT IC50 = 5-2853nM), an observation that has not previously been made (Figure B). Next, we tested the synergy of the combination of selinexor and venetoclax in the XPO1 mutant and wildtype cell lines. Increasing concentrations of the individual drugs were applied to each individual cell line in a 6x6 matrix. The cell viability percentage for each concentration was then entered into a synergy finder (www. synergyfinder.fimm.fi). The Bliss Independence model was used to calculate synergy of the Selinexor-Venetoclax combinations. As hypothesized, the combination of selinexor and venetoclax indeed showed synergy in both the wildtype and mutant XPO1 cell lines. Furthermore, the XPO1 mutant cell lines showed a higher degree of synergy compared to the wildtype cells (Figure C). Finally, a remarkable patient allowed us to test this combination ex vivo. This patient with CLL had undergone multiple therapies including chemoimmunotherapy, ibrutinib and venetoclax monotherapies. This patient had a founder XPO1 E571K mutation and also had acquired a BTK C481S ibrutinib resistance mutation and MYC amplification. These cells were unique in that they were easily able to be tested in ex-vivo culture to test sensitivity to different therapies. When tested with chemotherapy or ibrutinib they were completely resistant, and even with venetoclax they were fairly resistant; however, they remained sensitive to XPO1 inhibition with Selinexor. Selinexor and venetoclax showed remarkable synergy measured by a BLISS delta score of 18.78 (Figure D). In conclusion, inhibiting the nuclear exporter XPO1 and the anti-apoptotic factor BCL2 is synergistic in both XPO1 wildtype and mutant lymphoma. XPO1 mutant lymphomas show increased sensitivity to both selinexor and venetoclax. Additionally, selinexor and venetoclax showed a higher degree of synergism in XPO1 mutant lymphoma cell lines and were highly synergistic in primary XPO1 mutant CLL patient cells ex vivo. This combination is highly promising as an all oral alternative for relapsed, refractory lymphoma. Next steps include preclinical testing in mouse models in vivo using XPO1 mutant and wildtype mice crossed with mice overexpressing BCL2. Figure Disclosures No relevant conflicts of interest to declare.

A Once Daily, Oral, Triple Combination of BTK Inhibitor, mTOR Inhibitor and IMiD for Treatment of Relapsed/Refractory Richter's Transformation and De Novo Diffuse Large B-Cell Lymphoma

A Once Daily, Oral, Triple Combination of BTK Inhibitor, mTOR Inhibitor and IMiD for Treatment of Relapsed/Refractory Richter's Transformation and De Novo Diffuse Large B-Cell Lymphoma

Identification of predictors of response to initial oral combination therapy in WHO-functional class II or III PAH patients: a post-hoc analysis of the AMBITION study

Abstract Background AMBITION Study (NCT01178073) provided the first long-term clinical evidence for initial combination therapy with ambrisentan and tadalafil (COMB) compared with monotherapy of either agent (MONO), and the results contributed to the ESC/ERS guidelines recommending initial combination therapy in PAH patients with low and intermediate risk. However, predictors of response to initial oral combination therapy to identify PAH patients who benefit most from it have not been assessed. Purpose To identify potential predictors of response to initial combination therapy with ambrisentan and tadalafil (COMB) in PAH patients with WHO-FC II or III in the AMBITION study. Methods We examined 302 COMB patients from the modified intention to treat (mITT) population enrolled in the AMBITION study (n=605). The mITT population includes PAH patients with risk factors related to heart failure with preserved ejection fraction (Ex-PAS) who were excluded from the primary analysis set (PAS). A responder (i.e. event-free subject) was defined as not having a clinical failure event. Univariate and multivariate analyses were performed to identify the factors associated with responders. Multivariate logistic regression analysis was used to determine independent risk for each factor that showed a significant difference between cohorts by interactive backward selection. Odds ratio (OR), 95% confidence intervals (CIs) and p-values are presented. Results Univariate analysis showed that responders tended to be lower age, female, typical PAH (i.e. PAS), absence of coronary artery disease, non-use of oxygen therapy, and have better baseline parameters (i.e., lower NT-proBNP, longer 6-minute walk distance, low Borg index, high SaO2, WHO-FC II). A multivariate logistic regression analysis showed that female gender (OR=2.669, 95% CI: 1.291–5.518, P=0.0081), use of aldosterone antagonist diuretics (OR=2.535, 95% CI: 1.027–6.257, P=0.0436), lower log NT-proBNP (OR=0.704, 95% CI: 0.524–0.944, P=0.0190), and longer 6-minute walk distance (OR=1.006, 95% CI: 1.002–1.010, P=0.0039) were independent predictors of response to initial combination therapy. Conclusion These findings suggest that initial combination therapy with ambrisentan and tadalafil is beneficial, especially in less severe typical PAH patients. It also demonstrates that there is a potential contributing factor (i.e. use of aldosterone antagonist diuretics) which is not listed in the risk assessment table of the ESC/ERS guidelines. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): AMBITION study was funded by GlaxoSmithKline (GSK; study number 112565; trial registration number: NCT01178073) and Gilead Sciences, Inc. This analysis was funded by both companies.

Combination therapy with macitentan and phosphodiesterase type-5 inhibitor (PDE5i) in pulmonary arterial hypertension (PAH): real-world data from OPUS and OrPHeUS

Abstract Introduction Guidelines for the management of PAH recommend combination therapy for most patients, yet real-world data on treatment patterns in PAH are limited. Purpose To describe the characteristics, safety and clinical outcomes of PAH patients newly treated with double combination therapy with macitentan and PDE5i in the OPsumit® USers (OPUS) Registry and the OPsumit® Historical USers cohort study (OrPHeUS) combined dataset. Methods OPUS is a prospective, US, multicentre, observational drug registry (NCT02126943) ongoing since April 2014. OrPHeUS was a retrospective, US, multicentre chart review (NCT03197688); Oct 2013–Mar 2017. This cohort included patients initiating combination therapy with macitentan and a PDE5i (in any order) ≤60 days apart. Baseline was defined as the start date of the second therapy (i.e., start of combination therapy). Patient characteristics at baseline, changes in 6-minute walk distance (6MWD) and WHO functional class (FC) from baseline to follow-up, safety and outcomes are described. Results Of the 4428 OPUS/OrPHeUS PAH patients initiating macitentan, 2490 received this in combination with a PDE5i; of these patients, 740 (29.7%) initiated macitentan and a PDE5i concurrently (≤60 days apart). Data on disease duration was recorded in 729 patients at baseline; of these, 588 (80.7%) patients were incident (≤6 months since diagnosis) and 141 (19.3%) were prevalent (&amp;gt;6 months since diagnosis); median time from diagnosis to start of combination therapy of was 1.4 (Q1=0.6, Q3=3.6) months. At baseline, median age was 60 (Q1=49, Q3=70) years and 73.6% of patients were female. Mean baseline 6MWD was 264.5 (SD=119.8) m, recorded in 240 (32.4%) patients. WHO FC was recorded at baseline for 347 (46.9%) patients; 263 (75.8%) were in FC III/IV. Median combination therapy exposure was 10.2 (Q1=3.4, Q3=21.8) months, with 58.8% of patients ongoing at data cut. Changes from baseline to follow up in FC and 6MWD are shown in the figure. There was ≥1 adverse event (AE) reported in 455 (61.5%) patients and ≥1 hepatic AE (HAE) in 76 (10.3%) patients. In total, 232 (31.4%) patients discontinued macitentan; 122 (16.5%) due to AEs, 4 (0.5%) due to HAEs, 98 (13.2%) not due to an AE/HAE, and 8 (1.1%) for unknown reasons. Of the 305 patients who discontinued combination therapy, 137 (18.5%) discontinued macitentan only, 73 (9.9%) discontinued PDE5i only, and 95 (12.8%) discontinued both drugs at the same time. Kaplan-Meier estimates (95% CI) showed that 60.7% (56.4, 64.8) of patients were free from hospitalisation and 88.7% (85.7, 91.1) were alive at 12 months. Conclusions In this real-world setting, less than one third of patients treated with macitentan received initial oral combination therapy, despite current expert consensus favouring such therapeutic approaches. Patients initiating macitentan+PDE5i ≤60 days apart had improved 6MWD and WHO FC from baseline to follow-up. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd