Comparison between adalimumab introduction and methotrexate dose escalation in patients with inadequately controlled psoriatic arthritis (CONTROL): a randomised, open-label, two-part, phase 4 study.

BACKGROUND: Many patients with psoriatic arthritis do not reach minimal disease activity (MDA) on methotrexate alone. This phase 4 open-label study aimed to compare attainment of MDA following introduction of adalimumab with methotrexate escalation in patients with psoriatic arthritis who do not reach MDA after an initial methotrexate course (≤15 mg every week). METHODS: CONTROL was a phase 4, randomised, two-part, open-label study conducted in 14 countries and 46 sites. We recruited patients with confirmed active psoriatic arthritis, naive to biologic disease-modifying antirheumatic drugs, with an inadequate response to 15 mg or less of methotrexate. In part 1, patients were randomly assigned (1:1) to receive either methotrexate 15 mg (oral or subcutaneous) every week with the addition of adalimumab 40 mg (subcutaneously) every other week (adalimumab plus methotrexate group) or methotrexate (oral or subcutaneous) escalation up to 25 mg every week (escalated methotrexate group). Randomisation was done using Interactive Response Technology and stratified by the duration of methotrexate treatment (≤3 months and >3 months). In this open-label study there was no masking; participants, people giving the interventions, those assessing outcomes, and those analysing the data were aware of group assignment. The primary endpoint was the proportion of patients who reached MDA at 16 weeks. After 16 weeks (part 2), patients who reached MDA (responders) had their current therapy maintained or modified, wheras patients who did not reach MDA (non-responders) had their therapy escalated until 32 weeks. The primary endpoint in part 2 was the proportion of patients who reached MDA at 32 weeks, analysed in all patients who received one or more doses of study drug. The study is registered with ClinicalTrials.gov, NCT02814175. FINDINGS: Between Aug 5, 2016, and March 19, 2020, 245 of 287 patients initially assessed were enrolled in the study (50% men and 50% women; 92% of patients were White). 123 patients were randomly assigned to receive adalimumab plus methotrexate and 122 patients to receive escalated methotrexate. All 245 patients were included in the primary analysis, and 227 completed part 1 and entered part 2. A significantly higher proportion of patients reached MDA at 16 weeks in the adalimumab plus methotrexate group (51 [41%] patients) compared with the escalated methotrexate group (16 [13%] patients; p<0·0001). Efficacy was generally maintained through 32 weeks for patients who reached MDA at 16 weeks, with 41 (80%) of 51 adalimumab responders and ten (67%) of 15 methotrexate responders maintaining MDA at 32 weeks. Of adalimumab non-responders, 17 (30%) of 57 patients reached MDA at 32 weeks after adalimumab escalation to every week dosing. Among methotrexate non-responders, 50 (55%) of 91 reached MDA after adalimumab introduction. In part 1, two patients in the adalimumab plus methotrexate group reported serious adverse events; and in part 2, one adalimumab responder, three adalimumab non-responders, and three methotrexate non-responders reported serious adverse events. No new safety signals were identified. INTERPRETATION: Results from this novel treatment-strategy trial support the addition of adalimumab over escalating methotrexate in patients with psoriatic arthritis not reaching MDA after an initial methotrexate course. Safety results were consistent with the therapies' known safety profiles. FUNDING: AbbVie.

Efficacy of transdermal delivery of liposomal micronutrients through body oil massage on neurodevelopmental and micronutrient deficiency status in infants: results of a randomized placebo-controlled clinical trial.

BACKGROUND: Micronutrient deficiency is a known cause of adverse neurodevelopment and growth. Poor adherence to oral regimes of micronutrient supplements is a known challenge during the implementation of supplementation programs. The present study evaluates the benefits of liposomal encapsulated micronutrient fortified body oils (LMF oil) that can be used for infant body massage in terms of neurodevelopment and prevention of deficiency. STUDY DESIGN: Double-blind randomized clinical trial. METHODS: A total of 444 healthy infants aged 4-7 weeks were randomized to receive either LMF oil (containing iron, vitamin D, folate, and vitamin B12) or placebo oil for gentle body massage till 12 months of age. Blood samples were collected at 6 and 12 months for transferrin saturation (TSAT), hemoglobin, and 25-hydroxy vitamin (25-OH-D) levels. Mental and motor development was assessed at 12 months using developmental assessment for Indian Infants (DASII). RESULTS: A total of 391 infants completed the study. There was no significant improvement in the hemoglobin in the intervention group at 12 months of age as compared to the placebo group [- 0.50 vs.-0.54 g%]. There was a marginally significant improvement in 25-OH-D at 12 months in the LMF oil group [+ 1.46vs.-0.18 ng/ml, p = 0.049]. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age [adjusted mean change + 0.11vs.-0.51 g%, p = 0.043]. The mental or motor developmental quotients in the intervention group were not significantly different from those in the placebo group. CONCLUSION: Use of LMF oil for prevention of nutritional deficiency did not offer significant protection against nutritional anemia but prevented vitamin D deficiency to some extent with improvement in 25-OH-D at 12 months. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age. The intervention did not result in significant improvement in mental or motor development. Further evaluation with increased doses needs to be undertaken. TRIAL REGISTRATION: CTRI no: CTRI/2017/11/010710 ; dated 30/11/2017.

Hospitalization rates among patients with cystic fibrosis using pancreatic enzyme replacement therapy.

We investigated the relationship between self-reported adherence to pancreatic enzyme replacement therapy (PERT), nutritional status, and all-cause hospitalization in cystic fibrosis (CF) patients with a record of PERT use. Association of self-reported annual PERT use rate (adherence) with annual hospital admission rate (HAR) and annual total hospital nights (THNs) were analyzed for 5301 children (2000-2012) and 13,989 adults (2000-2013) from the CF Foundation Patient Registry. Multivariate linear regression was used to determine the association of HAR and THN with mean annual PERT use rate, cumulative PERT use rate, mean body mass index (BMI) (adult) or BMI percentile (pediatric), age, and sex. The median annual PERT use rate was 87% in children and 80% in adults. Statistically, higher annual PERT use, longer cumulative PERT, and higher BMI percentile (children) or BMI (adults) were significantly (p < 0.0001) associated with lower annual HAR and fewer annual THN in children and adults. Female sex was associated with higher annual HAR and more annual THN in children and adults (p < 0.05). Results indicate self-reported adherence to PERT, increased BMI, and male sex were associated with fewer hospital admissions and annual hospital nights in CF patients.

Development and Implementation of Liposomal Encapsulated Micronutrient Fortified Body Oil Intervention for Infant Massage: An Innovative Concept to Prevent Micronutrient Deficiencies in Children.

Indian communities have the ancient cultural practice of gentle oil massage for infants which has been shown to play a beneficial role in neuro-motor development. The concept of incorporating nanosized liposomes of micronutrients (i.e., iron, folate, vitamin B12, and vitamin D) in the body oil leverages this practice for transdermal supplementation of essential micro-nutrients. This paper describes the experience of developing an intervention in the form of body oil containing nanosized liposomes of iron and micro-nutrients built on the social context of infant oil massage using a theory of change approach. The process of development of the intervention has been covered into stages such as design, decide and implement. The design phase describes how the idea of nanosized liposomal encapsulated micronutrient fortified (LMF) body oil was conceptualized and how its feasibility was assessed through initial formative work in the community. The decide phase describes steps involved while scaling up technology from laboratory to community level. The implementation phase describes processes while implementing the intervention of LMF oil in a community-based randomized controlled study. Overall, the theory of change approach helps to outline the various intermediate steps and challenges while translating novel technologies for transdermal nutrient fortification to community level. In our experience, adaptation in the technology for large scale up, formative work and pilot testing of innovation at community level were important processes that helped in shaping the innovation. Meticulous mapping of these processes and experiences can be a useful guide for translating similar innovations.

Stable Liposome in Cosmetic Platforms for Transdermal Folic acid delivery for fortification and treatment of micronutrient deficiencies.

Oral folate fortification has been successful in many developed nations, however, developing countries still face low compliance and high incidence of folate deficiency associated with low birth weight infants and preterm deliveries. We report safe and efficient approach for transdermal systemic folate delivery using fluidising liposomes (120 ± 4 nm) stabilised within 3D matrix of naturally occurring cosmetic bases: Fuller's earth and henna with room temperature stability. The proof of stratum corneum fluidisation was established ex-vivo by Langmuir-Blodgett film, FTIR and confocal imaging in rat skin. In-vivo topical application in rats showed 11-fold increase in plasma folate within 2 hr, confirming systemic delivery through skin. Efficacy study in folate deficient rats over 4 weeks showed significantly higher plasma levels compared to oral delivery with significant skin depot. Sub-acute toxicity studies in rats at 750-fold higher doses showed safety after 4 weeks daily application. Primary irritation patch test on 25 healthy human volunteers proved non-irritant nature of the nutricosmetics. The technology is first demonstration of transdermal folate fortification with nanosized liposome incorporated in cosmetics, without synthetic surfactants/ethanol or need of external energy. The platform technology opens the possibility of delivering multiple nutrients systemically through skin and can be scaled for affordable community fortification.

Relationship of Initial Pancreatic Enzyme Replacement Therapy Dose With Weight Gain in Infants With Cystic Fibrosis.

OBJECTIVE: The aim of the study is to test the hypothesis of a positive relationship between initial dose of pancreatic enzyme replacement therapy (PERT) in infants with cystic fibrosis (CF) and optimal weight gain over the first 2 years of life. METHODS: Using the CF Foundation Patient Registry, we identified 502 children born in 2010 and used multivariable models to compare as our primary analysis their 2-year changes in weight-for-age z score (WAZ) and as our secondary analysis weight-for-length percentile (W/L%) by initial PERT dose. We focused on initial dose without reference to subsequent changes in treatment to avoid confounding by indication (severity). RESULTS: Initial PERT dose demonstrated a linear relationship to change in WAZ and W/L% at age 2 years. An initial dose of >1500 lipase units/kg/largest meal resulted in a higher likelihood of attaining WAZ at 2 years at or above the birth WAZ (adjusted odds ratio [aOR] 1.87, 95% confidence interval [CI] 1.22-2.86) and at the top quartile for improvement over 2 years in WAZ (aOR 1.90, 95% CI 1.19-3.05). There was no correlation between initial PERT dose and weight at initial PERT encounter (P = 0.35). Findings were similar for W/L% and when the cohort was restricted to infants who began PERT in the first 3 months of life. CONCLUSIONS: Infants receiving higher initial PERT dose demonstrate better weight-related outcomes, as reflected by attainment of favorable changes in WAZ and W/L%, at age 2 years.

Stratum corneum modulation by chemical enhancers and lipid nanostructures: implications for transdermal drug delivery.

Skin is the outermost and largest protective covering of the body. The uppermost layer of the skin, stratum corneum also called the horny layer is composed of keratin-filled cells covered by a lipid matrix which shields the skin from physical and chemical entrants. The lipid lamellar structure comprises of ceramides, cholesterol, fatty acids and proteins. Chemical enhancers that mimic the lamellar chemistry, reversibly fluidize the latter can be utilized for enhancing transport of cargo across the epidermis into the dermis. This review deals with the stratum corneum chemistry, mechanisms to modulate its packing with the aid of chemical enhancers, biophysical techniques for characterization and applications in the design of nature-inspired biocompatible lipid nanostructures for transdermal delivery of drugs and bioactive agents.

Efficacy and safety of ombitasvir/paritaprevir/r and dasabuvir compared to IFN-containing regimens in genotype 1 HCV patients: The MALACHITE-I/II trials.

BACKGROUND & AIMS: Telaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV. METHODS: Treatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12-36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies. RESULTS: Three hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0-1% and 8-11%, respectively, p<0.05) and rates of hemoglobin decline to <10g/dl (0-4% and 34-47%, respectively, p<0.05) were lower for OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. CONCLUSIONS: Among non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12week, multi-targeted OBV/PTV/r+DSV±RBV regimens and 66-82% with 24-48 total weeks of TPV+PegIFN/RBV. OBV/PTV/r+DSV±RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.

Exploratory trial of ombitasvir and ABT-450/r with or without ribavirin for HCV genotype 1, 2, and 3 infection.

OBJECTIVES: To examine the safety and efficacy of ombitasvir and ABT-450 with ritonavir (ABT-450/r) ± ribavirin (RBV) in treatment-naïve, non-cirrhotic adults with chronic HCV genotype 1-3 infection. METHODS: Patients in this open-label, exploratory, phase 2, multicenter study received ombitasvir (25 mg QD) and ABT-450/r (200/100 mg QD) ± RBV for 12 weeks. Primary efficacy endpoint was HCV RNA < lower limit of quantitation (LLOQ) from week 4 through 12. Sustained virologic response 12 weeks post-treatment (SVR12) was a secondary endpoint. RESULTS: Sixty-one patients were enrolled. Among genotype 1-, 2-, and 3-infected patients, respectively, HCV RNA was