PaTH Forward: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of TransCon PTH in Adult Hypoparathyroidism.

CONTEXT: Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. OBJECTIVE: This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. METHODS: This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day). RESULTS: By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 µg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events. CONCLUSION: TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

Evaluation of the Efficacy of Supplementation with Planox® Lemon Verbena Extract in Improving Oxidative Stress and Muscle Damage: A Randomized Double-Blind Controlled Trial.

Excessive exercise load can cause muscle soreness and fatigue, as well as inflammation and oxidative stress. Lemon verbena (Aloysia triphylla; Lippia citriodora) is often used as a spice in tea or beverages. Its leaves are rich in polyphenols, which have antioxidant and anti-inflammatory bioactivities. In the present study, we investigated whether supplementation with Planox® lemon verbena extract (LVE) could improve muscle damage and biochemical indicators after exhaustive exercise challenge. All subjects (30 males and 30 females) underwent a double-blind trial and were randomly divided into a placebo group (0 mg/human/day) and an LVE supplement group (400 mg/human/day), with gender-equal distribution. All subjects started supplementation 10 days before exhaustive exercise and continued it until all tests were completed. Before the intervention, after the exhaustive exercise, and on the following 3 days, the participants underwent 12-minute Cooper running/walking; blood collection; assessments of pain, muscle stiffness, maximum jump heights, and isometric maximum muscle strength. The results showed that supplementation with LVE effectively increased GPx and reduced CK, IL-6, 8-OHdG and muscle pain after the exhaustive exercise, but it had significant effect on strength recovery. In summary, LVE is a safe and edible natural plant extract that can reduce muscle damage and soreness after exercise. This trial was registered at clinicaltrials.gov as NCT04742244.

Improvement of Shen'ge formula on heart function in diastolic heart failure: A protocol for randomized, double-blind, placebo-controlled clinical study.

INTRODUCTION: Diastolic heart failure (DHF) is an important pathological type of heart failure, that involves multiple organ dysfunction and multiple complications. The prevalence of DHF is high, and effective treatments are lacking. Chinese herbs are an alternative therapy for DHF. Shen'ge formula (SGF) is a classical formula from which patients can benefit, but convincing evidence of its efficacy is lacking. Therefore, we designed this randomized controlled trial protocol. METHODS/DESIGN: This randomized, double-blind, placebo-controlled clinical trial will evaluate the efficacy and safety of SGF in the treatment of DHF. A total of 130 patients with DHF will be enrolled in the trial and treated with SGF granules or placebo for 12 weeks and followed up for 12 weeks. The primary outcome measurement will be to changes in plasma N-terminal brain natriuretic peptide precursor before versus after treatment, while the second primary outcome measurement will be changes in heart function before versus after treatment and the 12-week follow-up period. It will also include echocardiography, a cardiopulmonary exercise test, cardiac function grading, traditional Chinese medicine syndrome score, and the Minnesota Heart Failure Quality of Life Scale. Adverse events will be evaluated throughout the trial. DISCUSSION: The results of this trial will demonstrate whether SGF could alleviate symptoms, improve cardiac function, reduce readmission rates, and improve quality of life of patients with DHF. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2000036533, registered on August 24, 2020.

Chinese herbal formula Xuefu Zhuyu for primary dysmenorrhea patients (CheruPDYS): a study protocol for a randomized placebo-controlled trial.

BACKGROUND: Epidemiological studies have shown that young women often suffer from primary dysmenorrhea (PD) which is a common cause that affects their routine work and quality of life. Chinese herbal medicine has been widely used for PD in China. A systematic review found that Xuefu Zhuyu (XFZY) has a promising effect on PD management, yet there is a dearth of high-quality evidence in support of this claim. We want to conduct a randomized controlled trial to evaluate the efficacy and safety of XFZY for PD patients. METHODS: This is a protocol for a multicenter, randomized, placebo-controlled trial. A total of 248 participants with PD will be recruited at 6 centers and randomized into two groups-a herbal treatment group and a placebo group. The participants will receive either XFZY or placebo, three times per day, for 3 menstrual cycles, with a 12-week follow-up. The primary outcome will be the mean change in pain intensity as measured by VAS, while the change in menstrual pain duration, the change in peak pain intensity as measured by VAS, the Cox Menstrual Symptom Scale (CMSS), quality of life EQ-5D-5L, cumulative painkiller consumption, and health economics will be included as secondary outcomes. Adverse events will also be reported. DISCUSSION: This protocol describes a multicenter, double-blind, randomized, placebo-controlled trial that investigates the efficacy and safety of XFZY for primary dysmenorrhea. Validated evaluation tools will assess dysmenorrhea severity. We believe that this research will provide important evidence regarding the use of XFZY to treat dysmenorrhea. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900026819 . Registered on 23 October 2019.

Evaluation of platelet-rich plasma on hair regrowth and lesional T-cell cytokine expression in alopecia areata: A randomized observer-blinded, placebo-controlled, split-head pilot study.

BACKGROUND: Platelet-rich plasma has shown some promise in the treatment of alopecia areata. OBJECTIVE: To evaluate the effect of platelet-rich plasma on hair regrowth and lesional T-cell cytokine expression in alopecia areata. METHODS: This was a randomized, placebo-controlled, split-head study involving 27 patients with alopecia areata (Severity of Alopecia Tool score ≥25%). Alopecia patches on either side of the scalp were randomized to receive 3 intradermal injections of platelet-rich plasma or normal saline at monthly intervals and evaluated 3 months after the last session. Lesional T-cell cytokine messenger RNA expression was compared pre- and posttreatment in the platelet-rich plasma-treated sites. RESULTS: The mean Severity of Alopecia Tool score did not change significantly compared with baseline with either platelet-rich plasma or placebo injections at any visit; however, the mean percentage reduction in the score in the platelet-rich plasma arm was more than in the placebo arm (9.05% ± 36.48% vs 4.99% ± 33.88%; P = .049) at final assessment. The mean interferon gamma (P = .001) and interleukin 17 cytokine (P = .009) messenger RNA expression decreased, whereas the mean interleukin 10 (P = .049) and FOXP3 (P = .011) messenger RNA expression increased significantly after platelet-rich plasma treatment. LIMITATIONS: Small sample size and a relatively short follow-up. CONCLUSION: Platelet-rich plasma was found to have limited efficacy in alopecia areata. However, it may play a role in restoring immune balance in the alopecic patches.

Electroacupuncture for the treatment of functional dyspepsia: A systematic review and meta-analysis.

BACKGROUND: Functional dyspepsia (FD) is a common functional gastrointestinal disease. Acupuncture, including electroacupuncture (EA) is widely used as a complementary and alternative treatment for patients with FD. This study aimed to explore the effectiveness of EA for the treatment of FD. METHODS: We searched Embase, PubMed, and the Cochrane Central Register of Controlled Trials (Cochrane Library) for randomized controlled trials of FD treated by EA from inception to February 3, 2020. Two reviewers will independently screen studies for data extraction and assess the quality and risk of bias. The Cochrane Collaboration's risk of bias tool, RevMan 5.3 software were used for meta-analysis. Data were pooled to calculate relative risk and 95% confidence intervals (CIs) of substantial improvement after treatment for dichotomous data and mean differences (SMDs) and 95% CIs for continuous data. RESULTS: Seven randomized clinical trials included 853 patients. This meta-analysis investigated the effectiveness of EA alone in the treatment of FD relative to sham-EA or pharmacologic medication (PM). The results showed that EA could significantly improve clinical symptoms. Compared with sham-EA, EA was more effective in reducing symptom scores (SMD -3.44, 95% CI -4.21 to -2.67) and increasing normal slow waves of electrogastrogram (SMD 0.93, 95% CI -0.30 to1.55). When EA was combined with PM, there was no significant difference in reducing symptom scores (SMD -0.18, 95% CI -0.51 to 0.16), increasing the effective rate of clinical symptoms (risk ratio 1.04, 95% CI 0.96 to 1.13), enhancing the level of plasma motilin (SMD 0.93, 95% CI -0.30 to1.55), and reducing gastric half-emptying time (SMD 0.02, 95% CI -0.16 to 0.20). The results also showed that there were very few adverse events reported. CONCLUSION: This meta-analysis suggests that EA is better than the placebo (sham-EA) in treating FD, and the therapeutic effect of EA on FD is equivalent to that of PM on FD. Compared with PM, EA for FD is safer and has fewer adverse reactions. Despite limitations due to the quality and number of the included studies, EA might be used as an effective and safe treatment for FD.

An Herbal Formulation of Jiawei Xiaoyao for the Treatment of Functional Dyspepsia: A Multicenter, Randomized, Placebo-Controlled, Clinical Trial.

INTRODUCTION: To investigate the efficacy and safety of an herbal formulation of Jiawei Xiaoyao (JX) on gastrointestinal symptoms in patients with functional dyspepsia (FD) who had previously rejected standard therapies of proton pump inhibitors, H2 blockers, or Helicobacter pylori eradication. METHODS: A total of 144 adult men and women with FD according to the Rome III criteria were recruited at 9 sites in China from August 2017 to April 2019. Participants were randomized to receive either a JX pill or placebo (12 g/d, 6 g twice a day) for 4 weeks. The primary end point was the change in the total Gastrointestinal Symptom Score (GIS) from baseline to week 4. The secondary end points included the scores on the Hamilton Depression Scale and the Hamilton Anxiety Scale. The safety outcomes included the results of the complete blood count, the liver function test, the renal function test, urinalysis, the fecal occult blood test, and an electrocardiogram. RESULTS: Data from 141 patients (JX pill, n = 70; placebo, n = 71) were statistically analyzed. The mean ± SD of the GIS for the JX pill group at baseline and 4 weeks was 9.3 ± 3.1 and 3.8 ± 3.0, respectively; the mean ± SD of the GIS for the placebo group at baseline and 4 weeks was 9.5 ± 3.4 and 5.3 ± 4.4, respectively (change from baseline to 4 weeks in the JX pill group vs change from baseline in the control group, -1.3 points; P = 0.013). The JX pill group showed greater improvement in both the Hamilton Depression Scale and Hamilton Anxiety Scale scores from baseline to 4 weeks than the placebo group, but the difference was not significant. The total number of adverse events was 30 in the JX pill group vs 20 in the placebo group (P = 0.240). DISCUSSION: The JX pill was superior to the placebo in terms of improving the GIS in patients with FD but did not significantly improve depression or anxiety symptoms. These findings suggest that the JX pill may have a positive effect on the resolution of gastrointestinal symptoms in patients with FD who are seeking alternative therapies.

The Effect of Conditioned Media From Human Adipocyte-Derived Mesenchymal Stem Cells on Androgenetic Alopecia After Nonablative Fractional Laser Treatment.

BACKGROUND: The conditioned media from adipocyte-derived mesenchymal stem cells-conditioned media (ADSC-CM) contains cytokines and growth factors that stimulate hair regeneration. OBJECTIVE: We evaluated the efficacy and safety of human ADSC-CM treatment on patients who underwent nonablative fractional laser for the treatment of androgenetic alopecia (AGA). MATERIALS AND METHODS: Thirty patients who underwent nonablative fractional laser treatment were topically administered either ADSC-CM or placebo solution. As a primary outcome, phototrichograms were taken to measure changes in hair density at each visit. In addition, global improvement scores (GISs) were compared by clinical digital photographs, which were taken at the initial and final visits, and assessed by 2 independent dermatologists. Finally, the investigator's improvement score was measured by questionnaire response during the final visit. RESULTS: Hair density comparisons during the treatment period revealed that the ADSC-CM group had significantly higher final densities compared with the placebo group. The GIS of the ADSC-CM group was also significantly higher than the placebo group. Finally, no adverse effects associated with the application of ADSC-CM were noted during the study. CONCLUSION: The application of ADSC-CM after nonablative fractional laser treatment accelerated increases in hair density and volume in AGA patients.

Probiotics for induction of remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, in which the pathogenesis is believed to be partly influenced by the gut microbiome. Probiotics can be used to manipulate the microbiome and have therefore been considered as a potential therapy for CD. There is some evidence that probiotics benefit other gastrointestinal conditions, such as irritable bowel syndrome and ulcerative colitis, but their efficacy in CD is unclear. This is the first update of a Cochrane Review previously published in 2008. OBJECTIVES: To assess the efficacy and safety of probiotics for the induction of remission in CD. SEARCH METHODS: The following electronic databases were searched: MEDLINE (from inception to 6 July 2020), Embase (from inception to 6 July 2020), the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane IBD Review Group Specialised Trials Register, World Health Organization (WHO) International Clinical Trials Registry, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared probiotics with placebo or any other non-probiotic intervention for the induction of remission in CD were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the methodological quality of included studies. The primary outcome was clinical remission. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for dichotomous outcomes. MAIN RESULTS: There were two studies that met criteria for inclusion. One study from Germany had 11 adult participants with mild-to-moderate CD, who were treated with a one-week course of corticosteroids and antibiotics (ciprofloxacin 500 mg twice daily and metronidazole 250 mg three times a day), followed by randomised assignment to Lactobacillus rhamnosus strain GG (two billion colony-forming units per day) or corn starch placebo. The other study from the United Kingdom (UK) had 35 adult participants with active CD (CDAI score of 150 to 450) randomised to receive a synbiotic treatment (comprised of freeze-dried Bifidobacterium longum and a commercial product) or placebo. The overall risk of bias was low in one study, whereas the other study had unclear risk of bias in relation to random sequence generation, allocation concealment, and blinding. There was no evidence of a difference between the use of probiotics and placebo for the induction of remission in CD (RR 1.06; 95% CI 0.65 to 1.71; 2 studies, 46 participants) after six months. There was no difference in adverse events between probiotics and placebo (RR 2.55; 95% CI 0.11 to 58.60; 2 studies, 46 participants). The evidence for both outcomes was of very low certainty due to risk of bias and imprecision. AUTHORS' CONCLUSIONS: The available evidence is very uncertain about the efficacy or safety of probiotics, when compared with placebo, for induction of remission in Crohn's disease. There is a lack of well-designed RCTs in this area and further research is needed.

Opposing needling for analgesia and rehabilitation after unilateral total knee arthroplasty: a randomized, sham-controlled trial protocol.

BACKGROUND: This randomized controlled clinical trial aims to evaluate the efficacy and safety of opposing needling in patients undergoing unilateral total knee arthroplasty (TKA). Opposing needling is one of the special needling methods used in acupuncture and moxibustion therapy. It involves needling acupoints on the contralateral side for pain management. Although, opposing needling is used for pain management in clinics, evidence to support its effectiveness as an analgesic after total knee arthroplasty is scant. We designed a randomized controlled clinical trial to evaluate efficacy and safety of opposing electroacupuncture (EA) in alleviating pain associated with unilateral total knee arthroplasty. METHODS/DESIGN: This is a protocol for a randomized controlled patient- and assessor-blinded trial with three parallel arms (A, opposing EA; B, operated side EA; C, sham EA). Yinlingquan (SP9), Yanglingquan (GB34), Futu (ST32), and Zusanli (ST36) acupoints are selected for all three groups. In group A, the healthy side will be treated with EA, while the operated side will be administered sham EA. In group B, the operated side will be treated with EA while on the healthy side sham EA will be used. For group C, sham EA will be used on both sides. All patients in the three groups will receive treatment once a day for 3 days. The post-operative pain measured using a visual analogue scale score (including pain while resting and being active) and the additional dose of the patient-controlled analgesic pump after operation will be recorded as the primary outcomes. Secondary outcomes such as knee function and swelling, range of motion (including active and passive range of motion), post-operative anxiety, and acupuncture tolerance will also be assessed. DISCUSSION: Opposing needling is a potential non-pharmacological treatment for relieving pain and improving functional rehabilitation after TKA, during which patients receive acupuncture on the healthy side rather than on the operated side. This sham controlled clinical trial, designed to evaluate efficacy and safety of opposing needling for patients after TKA, will provide evidence for pain management and functional rehabilitation after unilateral TKA. TRIAL REGISTRATION: ChiCTR, ChiCTR1800020297 (http://www.chictr.org.cn/edit.aspx?pid=34231&htm=4). Registered 22 December 2018.

Vitamin D supplementation compared to placebo in people with First Episode psychosis - Neuroprotection Design (DFEND): a protocol for a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: People experiencing their first episode of psychosis are often deficient in vitamin D. Observational studies have reported an association between low vitamin D concentrations and poorer subsequent health outcomes in psychosis. A vitamin D deficiency in neonates and children has been linked to a later increased risk of schizophrenia and psychotic-like experiences. This trial aims to examine the effect of high-dose vitamin D supplementation on outcomes in early psychosis. We hypothesise that vitamin D supplementation will be associated with better mental health outcomes. METHODS/DESIGN: The DFEND study is a multicentre double-blind placebo-controlled parallel-group trial of vitamin D supplementation in people with early psychosis. Patients with an ICD-10 diagnosis of functional psychosis will be randomised in a 1:1 ratio to receive either 120,000 IU/month of vitamin D (cholecalciferol) or a matched placebo for 6 months. The primary outcome is the total Positive and Negative Syndrome Scale (PANSS) score at the 6-month follow-up for all patients. Secondary outcomes include assessment of mood (Calgary Depression Scale), general function (Global Assessment of Functioning), cardiovascular risk (body mass index, waist circumference, C-reactive protein, cholesterol and HbA1c) and vitamin D levels at the 6-month follow-up. Additionally, 3- and 6-month total PANSS scores will be analysed for those with inadequate vitamin D levels at the baseline. DISCUSSION: The DFEND study is the first trial to examine whether vitamin D supplementation in early psychosis is associated with better mental health outcomes. The findings of this study may help to resolve the clinical equipoise regarding the benefits and cost-effectiveness of routine vitamin D supplementation in people with psychosis. TRIAL REGISTRATION: ISRCTN, ISRCTN12424842. Registered on 25 February 2015.

Effects of sang-qi granules on blood pressure and endothelial dysfunction in stage I or II hypertension: study protocol for a randomized double-blind double-simulation controlled trial.

BACKGROUND: Worldwide, hypertension is an important public health challenge because of its high prevalence and the concomitant risks of cardiovascular disease. It induces half of the coronary heart disease and approximately two-thirds of the cerebrovascular disease burden. Vascular endothelial dysfunction has important roles in the pathophysiology of essential hypertension. Types I and II hypertension can be treated with sang-qi granules (SQG), a Chinese herbal formula. Several experimental studies on animals have shown that SQG can lower blood pressure and myocardial fibrosis by suppressing inflammatory responses. However, no standard clinical trial has confirmed this. Whether SQG can improve endothelial cell function is unknown. METHODS/DESIGN: In this randomized double-blind double-simulation controlled trial, 300 patients with stage I or II hypertension will be recruited and randomly allocated in a 1:1:1 ratio to group A (treatment with SQG and placebo instead of Losartan), group B (treatment with Losartan and placebo instead of SQG), and group C (treatment with SQG and Losartan). In this study, 10 g of SQG (or its placebo) will be administrated twice a day and 50 mg of Losartan (or its placebo) will be administrated once in the morning. The primary endpoint is the drug efficiency for each of the three groups. The secondary endpoints are the change in average systolic and diastolic blood pressure during the day and the night, the change in the rate at which blood pressure drops at night, assessment of target organ damage (heart rate variability, ankle-brachial pressure index, and pulse wave velocity), assessment of any improvement in symptoms (Hypertension Symptom Scale, syndrome integral scale in traditional Chinese medicine, Pittsburgh Sleep Quality Index Scale, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and the 36-Item Short Form Health Survey), blood lipids, serum indicators of vascular function (changes in serum levels of ET-1, TXA2, NO, and PGI2), and safety indicators. DISCUSSION: This study aims to provide clinical evidence on the efficacy and safety of SQG in the treatment of hypertension. Moreover, the possible mechanism by which SQG may lower blood pressure will be explored by observing the protective effect of SQG on vascular endothelial function, as well as its effect on related clinical symptoms, risk factors, and the target organs of hypertension. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR1800016427. Registered on 1 June 2018.

The effect of oral hydrolyzed eggshell membrane on the appearance of hair, skin, and nails in healthy middle-aged adults: A randomized double-blind placebo-controlled clinical trial.

BACKGROUND: Many over the counter and consumer packaged goods are promoted to enhance the appearance of hair, skin, and nails for the consumer. Nutrition is a major factor in affecting the health and appearance of hair, skin, and nails. In addition to how one eats, dietary supplementation may play a role in overall health and in the physical appearance. AIMS: It was the aim of this study to objectively and subjectively evaluate the impacts of a nutritional intervention as compared to placebo on the appearances of hair, skin, and nails in healthy middle-aged adults. METHODS: Randomized, double-blind placebo-controlled study with 88 subjects randomized evenly to Study Product (BiovaBio™ 450 mg/d, n = 44) or Placebo (n = 44) for 12-weeks. Outcome tests included TrichoScan HD (hair), Canfield Visia® -CR (skin), modified FACE-Q (skin), and anchored Likert Scales (nails). RESULTS: Oral hydrolyzed eggshell membrane ingestion was associated with a significant improvement in facial skin appearance in crow's feet in 4 weeks and skin tone in 8 weeks, with significant impact on hair thickness, reduction in hair breakage and improvement in hair growth at 4, 8, and 12 weeks. There were no observed subjective improvements for nails (appearance, strength or growth). CONCLUSIONS: Oral supplementation of 450 mg/d hydrolyzed eggshell membrane for 12 weeks is associated with improvement in the appearance of facial skin and hair.

A Double-Blind, Placebo-Controlled Trial to Assess Safety and Tolerability of (Thetanix) Bacteroides thetaiotaomicron in Adolescent Crohn's Disease.

INTRODUCTION: Thetanix (gastroresistant capsules containing lyophilized Bacteroides thetaiotaomicron) is a live biotherapeutic, under development for Crohn's disease, that antagonizes transcription factor nuclear factor kappa B, reducing proinflammatory cytokines, particularly tumor necrosis factor alpha. We aimed to assess safety and tolerability in adolescents with Crohn's disease in remission. METHODS: Subjects who were 16-18 years with Crohn's in remission (weighted pediatric Crohn's disease activity index <12.5) were recruited. Each active dose comprised ∼108.2±1.4 colony forming units of B. thetaiotaomicron (randomized 4:1 active:placebo). Part A was single dose. Part B involved 7.5 days twice daily dosing. Serial stools were analyzed for calprotectin, 16S rRNA sequencing, and B. thetaiotaomicron real-time polymerase chain reaction. Bloods were taken serially. Subjects reported adverse events and recorded temperature twice daily. RESULTS: Fifteen subjects were treated-8 in part A (75% men, median 17.1 years) and 10 in part B, including 3 from part A (80% men, median 17.1 years); all 18 completed. Seventy percent took concurrent immunosuppression. Reported compliance was >99% in part B. Two subjects reported adverse events deemed related-one in part A with eructation, flatulence, and reflux; one in part B with dizziness, abdominal pain, and headache. No serious adverse events were reported. There was no significant change in median calprotectin across part B (87.8 [4.4-447] to 50.5 [5.3-572], P = 0.44 by the Fisher exact test in the active group). No significant differences were found in microbiota profiles, but diversity seemed to increase in treated subjects. DISCUSSION: Thetanix, after single and multiple doses, was well tolerated. Although the numbers in this study were small, the safety profile seems good. Future studies should explore efficacy.

Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension.

BACKGROUND & AIMS: Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contribute to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. METHODS: Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n = 54), 8 mg/kg (n = 54), or placebo (n = 54) for 52 weeks. The primary endpoint was change in HVPG (Δ HVPG) at the end of the 52-week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. RESULTS: We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (-0.28 mm HG vs 0.10 mm HG, P = 1.0) or between the 8 mg/kg belapectin and placebo group (-0.25 mm HG vs 0.10 mm HG, P = 1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n = 81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P = .02) and reduced development of new varices (P = .03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. CONCLUSIONS: In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices. ClinicalTrials.gov number: NCT02462967.

A Combination of Tamarindus indica seeds and Curcuma longa Rhizome Extracts Improves Knee Joint Function and Alleviates Pain in Non-Arthritic Adults Following Physical Activity.

Background: Knee joint pain is the most common reason for physical disability which associates with age. TamaFlexTM (NXT15906F6) is a synergistic anti-inflammatory formulation which contains ethanol/aqueous extracts of Tamarindus indica seeds and ethanol extract of Curcuma longa rhizome. Methods: In a 90-day randomized, double-blind, placebo-controlled study, we evaluated efficacy of NXT15906F6 in relieving pain and improving joint function in non-arthritic adults. Ninety non-arthritic subjects who experienced knee pain and joint discomfort following a six-minute walk test (SMWT) and Stair climb test (SCT) participated in the present trial. Subjects received either 250 mg (n=30) or 400 mg (n=30) of NXT15906F6 or matched placebo (PL: n=30) daily for 90 days. Improvement from baseline six-minute walk distance (SMWD) in NXT15906F6 groups, compared with placebo (PL) was the primary outcome of the study. Results: At post-intervention, subjects in NXT15906F6-250 (p<0.001) and NXT15906F6-400 (p<0.0001) groups showed substantial improvements in mean changes of SMWD from baseline compared to placebo. The 250 mg and 400 mg NXT15906F6 groups also improved average walking speed from baseline by 0.08±0.07 m/s (p=0.0010) and 0.11±0.08 m/s (p<0.0001), respectively. The NXT15906F6 groups experienced significant improvement in SMWT performances as early as 14 days. NXT15906F6-supplemented participants showed a consistent benefit of pain relief and improved musculoskeletal functions, compared to placebo. Conclusion: NXT15906F6 provided substantial relief from knee pain after physical activity and improved joint function in non-arthritic adults. Study participants did not show any major adverse events, and they tolerated well this novel herbal formulation.

Cost-Effectiveness of Cabozantinib in the Second-Line Treatment of Advanced Hepatocellular Carcinoma.

BACKGROUND: Treatment options are limited for patients with advanced hepatocellular carcinoma (HCC) that progresses after treatment with sorafenib. Cabozantinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, recently showed improved overall survival (OS) compared with placebo in sorafenib-pretreated patients with advanced HCC in the CELESTIAL trial. This study assessed the cost-effectiveness of cabozantinib for second-line treatment of patients with advanced HCC from a US healthcare system perspective. PATIENTS AND METHODS: Cost and utility data were extracted from the CELESTIAL trial and used to determine the cost-effectiveness of cabozantinib compared with placebo plus best supportive care. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) gained by using cabozantinib compared with placebo plus best supportive care in sorafenib-pretreated HCC. RESULTS: In the base-case analysis using data from the CELESTIAL trial, the incremental QALY and ICER were 0.067 and $1,040,675 for cabozantinib compared with placebo and best supportive care. OS reported in the CELESTIAL trial (hazard ratio, 0.76; 95% CI, 0.63-0.92) had the strongest association with the ICER. In one-way sensitivity analyses, there were no scenarios in which cabozantinib was cost-effective. In a cost-threshold analysis, cabozantinib would have to be priced at least $50 per pill to be cost-effective considering a willingness to pay of $100,000 per QALY. Although the CELESTIAL trial demonstrated that cabozantinib improves OS compared with placebo in patients with HCC that progresses after treatment with sorafenib, our analysis shows that cabozantinib is not a cost-effective therapy in this scenario. CONCLUSIONS: At current costs, cabozantinib is not cost-effective for second-line therapy of HCC in the United States.

Anti-sebum efficacy of guava toner: A split-face, randomized, single-blind placebo-controlled study.

BACKGROUND: Guava has benefit phytochemicals that are important for skin-disorder treatment. Nevertheless, its efficacy against oily skin has never been reported. AIMS: The guava toner was developed and clinical evaluated. METHODS: The base toner was formulated, accelerated stability tested, and sensory-evaluated in 10 volunteers. The highest preference base was incorporated with guava extract, stability examined, and skin irritation assessed in 21 volunteers by a single application close patch test. Anti-sebum efficacy was split-face, randomized, single-blind placebo-controlled evaluated in 21 volunteers for 28 days and monitored by Sebutape® on forehead and nose. RESULTS: The stable toner base with the greatest preference (83.20 ± 1.85%) was incorporated with 3%, 4.5%, and 6% of guava extract. The toners were stable with none of skin irritation. The toner with 6% guava extract was selected for efficacy evaluation. Guava toner significantly reduced oiliness of forehead (13.10 ± 3.67%, P < 0.05) and nose (21.43 ± 3.21%, P < 0.001) better than the base toner. The activity on nose was significantly noted (10.72 ± 3.51%, P < 0.05) since the 3rd week of application. CONCLUSIONS: Anti-sebum guava toner was efficiently evidence approved and suitable for a daily application to improve the efficacy.

Sorafenib in Hepatopulmonary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.

The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar-arterial oxygen gradient (AaPO2 ) at 3 months in patients with HPS. We performed a randomized, double-blind, placebo-controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, -3.8 to 7.0 mm Hg) and those allocated to placebo (-2.4 mm Hg; IQR, -4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2-expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated.

Fish Oil Increases Specialized Pro-resolving Lipid Mediators in PAD (The OMEGA-PAD II Trial).

BACKGROUND: N-3 polyunsaturated fatty acid (PUFA) supplementation has been associated with reduced mortality and inflammation in patients with cardiovascular disease. There are limited data on the effects of n-3 PUFA supplementation in patients with peripheral artery disease (PAD). MATERIALS AND METHODS: The OMEGA-PAD II trial was a double-blinded, randomized, placebo-controlled trial to assess the effect of 3 mo of high-dose oral n-3 PUFA supplementation on inflammation, endothelial function, and walking ability in patients with PAD. RESULTS: Twenty-four patients with claudication received 4.4 g/d of fish oil or placebo for 3 mo. Outcomes measured included high-sensitivity C-reactive protein levels, the omega-3 index, endothelial function as measured via flow-mediated vasodilation, walking impairment questionnaire, and a 6-min walk test. Plasma levels of specialized pro-resolving lipid mediators (SPMs) were measured by liquid-chromatography-tandem mass spectrometry. In patients treated with fish oil, the absolute mean omega-3 index significantly increased from baseline (fish oil: 7.2 ± 1.2%, P < 0.001; placebo: -0.4 ± 0.9%, P = 0.31; between-group P < 0.001). Furthermore, there were significant increases in several pathway markers of SPM biosynthesis, including several mono-hydroxyeicosapentaenoic acids and mono-hydroxydocosahexaenoic acids. We also observed significant increases in the SPM lipoxin A5 (fish oil: 0.57 ± 0.70 pg/mL, P = 0.05; placebo: 0.01 ± 0.38 pg/mL, P = 0.93; between-group P = 0.04) and resolvin E3 (fish oil: 154 ± 171 pg/mL, P = 0.04; placebo: 32 ± 54 pg/mL, P = 0.08; between-group P = 0.04). There were no significant changes in high-sensitivity C-reactive protein, flow-mediated vasodilation, walking impairment questionnaire, or 6-min walk test in the fish oil group. CONCLUSIONS: Fish oil increases SPMs in plasma of patients with PAD. Further studies are required to determine whether these early changes translate to clinical improvements in patients with PAD.