Despite improving survival rates, people with advanced cancer face several physical and psychosocial concerns. Leisure-time physical activity (LPA) has been found to be beneficial after cancer diagnosis, but little is known about the current state of research exploring LPA in advanced cancer. Our objectives were to (a) map the literature examining LPA in people with advanced cancer, (b) report on the terms used to describe the advanced cancer population within the literature, and (c) examine how the concept of LPA is operationalized within the literature.

Our scoping review followed Arksey and O'Malley's methodological framework. We performed a search of 11 electronic databases and supplementary sources (February 2018; database search updated January 2020). Two reviewers independently reviewed and selected articles according to the inclusion criteria: English-language journal articles on original primary research studies exploring LPA in adults diagnosed with advanced cancer. Descriptive and thematic analyses were performed.

Ninety-two articles met our criteria. Most included studies were published in the last decade (80%) and used quantitative methods (77%). Many study populations included mixed (40%), breast (21%), or lung (17%) cancers. Stages 3–4 or metastatic disease were frequently indicated to describe study populations (77%). Several studies (68%) described LPA programs or interventions. Of these, 78% involved structured aerobic/resistance exercise, while 16% explored other LPA types.

This review demonstrates a recent surge in research exploring LPA in advanced cancer, particularly studies examining exercise interventions with traditional quantitative methods. There remains insufficient knowledge about patient experiences and perceptions toward LPA. Moreover, little is known about other leisure activities (e.g., Tai Chi, dance, and sports) for this population. To optimize the benefits of LPA in people with advanced cancer, research is needed to address the gaps in the current literature and to develop personalized, evidence-based supportive care strategies in cancer care.

Les troubles dépressifs concernent près de deux fois plus de femmes que d’hommes [1]. Cette prévalence pourrait être due à une sensibilité accrue des femmes aux émotions négatives [2]. Peu d’études d’imagerie cérébrale ont comparé l’activité cérébrale des hommes et des femmes lors de la présentation de stimuli émotionnels.

Notre objectif était d’étudier les activations cérébrales des hommes et des femmes lors d’une tâche émotionnelle. Nous avons émis l’hypothèse que le pattern d’activations cérébrales diffère selon le sexe des individus et la valence des stimuli.

Nous avons mené une étude en imagerie par résonance magnétique fonctionnelle (IRMf) chez 30 participants sains (15 hommes et 15 femmes). Des stimuli à valence positive, négative et neutre étaient présentés aux sujets. Les participants ont évalué subjectivement la valence et l’intensité des stimuli.

Nous observons une activité plus importante chez les femmes que chez les hommes dans plusieurs régions clés du traitement des émotions lors de la présentation de stimuli négatifs. Aucune différence significative entre les hommes et les femmes n’a été relevée concernant l’évaluation subjective des stimuli en termes de valence et d’intensité.

Les résultats suggèrent qu’il existe bien une différence de patterns d’activation entre les hommes et les femmes lors de la perception des émotions négatives, qui irait dans le sens d’une sensibilité accrue chez les femmes. Celle-ci pourrait expliquer leur plus grande vulnérabilité aux troubles dépressifs. Il pourrait être intéressant de répliquer cette étude chez des patients qui souffrent de troubles de l’humeur.

In 2016, the US FDA issued an industry guidance document “Quality Attribute Considerations for Chewable Tablets” which describes the quality attributes to be considered when developing chewable tablets. It includes recommendations on selection of acceptance criteria for measuring palatability (having a taste acceptable to the patient or has adequate masking). These data are now recommended as part of ANDA submissions. Palatability is a known positive contributing factor to drug adherence and persistence. We summarize here palatability data for a new amphetamine extended-release tablet (Dyanavel XR® Extended Release Tablet; AMPH ER TAB).

This was a 2-arm preplanned secondary analysis from a comparative bioavailability study: single-dose AMPH ER TAB 20 mg chewed under fasting (Treatment A) and fed (Treatment B) conditions. Subjects rated the palatability of AMPH ER TAB (Treatments A+B) through a 5-question palatability questionnaire. The questions included in the palatability questionnaire were as follows:

1. 1. Oral sensation/mouth feel of the drug product

2. 2. Taste of the drug product

3. 3. How strong is the taste?

4. 4. Aftertaste of the product

5. 5. How strong is the aftertaste?

Subjects completed the questionnaire within 10 minutes from the time of drug administration, which was evaluated and scored according to the rubric below:

Q1, Q2, Q4: palatability- Very unpleasant (score of 1), Unpleasant (2), No sensation or mouthfeel (3), Pleasant (4), and Very pleasant (5)

Q3, Q5 (Taste/aftertaste strength): Very strong (score of 1), Strong (2), Moderate (3), Mild (4), No aftertaste (5).

Scores of 1-2 for both categories were Negative; score of 3 was Neutral, and 4-5 were Positive.

35 subjects comprised the palatability dataset (completed one question on the questionnaire). In the palatability analysis, for treatments A and B, most of the subjects rated the oral sensation/mouth feel of AMPH ER TAB (Question 1) and the taste of AMPH ER TAB (Question 2) as positive (pleasant to very pleasant) (70.1% and 83.6%, respectively).

When evaluating taste strength (Question 3): 43.3% rated the strength as positive (mild/no taste) and 43.3% of subjects rated the strength as neutral (moderate taste). Also, 82.1% rated the aftertaste of AMPH ER TAB (Question 4) as positive (pleasant/very pleasant) and 52.2% rated the strength of the aftertaste as positive (mild/no taste).

Most subjects rated the oral sensation and taste as pleasant or very pleasant, whether chewed under fasted conditions or after a meal. With respect to the taste strength, most subjects rated it as moderate (chewed under fasted conditions) or mild/no taste (chewed after a meal). Aftertaste was rated as pleasant or very pleasant in most subjects, with the strength as moderate (chewed under fasted conditions) or mild/no aftertaste (chewed after a meal). AMPH ER Tablets provided an overall pleasant taste and mouthfeel experience for patients.

Funding Acknowledgements: Tris Pharma, Inc.

Evaluate comparative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB, Tris Pharma, Inc., Monmouth Junction, NJ) 20 mg, swallowed whole or chewed and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; and evaluate whether a PK food effect exists on AMPH ER TAB (contains a 3.2:1 ratio of d- to l-amphetamine).

Healthy volunteers (18-55 yr) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted).

A crossover design was used. Samples were collected each period pre-dose and at time points to 60 h post-dose. D-and l-amphetamine were measured, and PK was calculated (90% CIs of the ratios of the geometric mean plasma levels) for Cmax, AUCt, and AUC0∞. Comparative bioavailability was determined when ratios were within 80 and 125%. Safety was also assessed.

32 subjects completed the study. Based on the calculated bioavailability ratios, for AMPH ER TAB swallowed vs. AMPH EROS fasted: d-amphetamine total and peak exposures were found to be similar: AUC0-t: 100.68-108.08%, AUC0-∞:101.47-109.52%, Cmax: 98.10-103.17%. For l-amphetamine, the total and peak exposures were similar: AUC0-t: 100.31-108.57%, AUC0-∞:101.27-111.09%, Cmax: 98.2-103.37%.

AMPH ER TAB chewed vs. AMPH EROS fasted: For d-amphetamine, the total and peak exposures were similar: AUC0-t: 99.23-106.62%, AUC0-∞: 99.58-107.59%, Cmax: 99.91-105.14%. For l-amphetamine, the total and peak exposure was similar: AUC0-t: 98.16-106.35%, AUC0-∞: 98.44-108.11%, Cmax: 99.53-104.75%.

Food effect: AMPH ER TAB, chewed, fasted vs. fed: For d-amphetamine, the total and peak exposure was similar: AUC0-t: 92.57-99.49%, AUC0-∞: 91.12-98.48%, Cmax: 94.22-99.17%.

For l-amphetamine, the total and peak exposure was similar: AUC0-t: 91.27-98.91%, AUC0-∞: 88.44-97.17%, Cmax: 94.52-99.50%).

No serious AEs were reported during the conduct of this study, and the AE profiles were observed to be similar in frequency of events and severity to other amphetamine formulations used in ADHD.

Bioavailability of single dose of AMPH ER TAB for both d- and l-amphetamine was comparable, swallowed whole or chewed, to an equivalent 20 mg dose of the reference product AMPH EROS, 2.5 mg/mL fasted, and showed equivalent peak and overall exposure.

No food effect was observed for AMPH ER TAB administered chewed. All AEs were mild in severity and AE profiles were similar to other amphetamine formulations used for treatment of ADHD.

Tris Pharma, Inc.

Evaluate the relative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB) 20 mg, swallowed whole or chewed, and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; evaluate food effect on AMPH ER TAB.

Healthy volunteers (18–55 years) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted). A crossover study design was used. Plasma samples were collected each period predose and at time points to 60 hours postdose. d- and l -amphetamine were measured and pharmacokinetic (PK) was calculated (90% confidence intervals of the ratios of the plasma levels) for AUC0-t , AUC0-∞, and C max. Comparative relative bioavailability between formulations was determined when ratios were within 80% and 125%. Safety was also assessed.

Thirty-two subjects completed the study. AMPH ER TAB swallowed versus AMPH EROS (fasted): for d- and l-amphetamine, the total and peak exposure was similar: d: AUC0-t : 100.68% to 108.08%, AUC0-∞: 101.47% to 109.52%, C max: 98.10% to 103.17%; l : AUC0-t : 100.31% to 108.57%, AUC0-∞: 101.27% to 111.09%, C max: 98.2% to 103.37%. For d- and l-amphetamine when the tablet is swallowed whole, T max was 5.00 hours (with a range of 2.00–9.00 hours). AMPH ER TAB chewed versus AMPH EROS (fasted): for d- and l-amphetamine, the total and peak exposure was similar: d: AUC0-t : 99.23% to 106.62%, AUC0-∞: 99.58% to 107.59%, C max: 99.91% to 105.14%; l: AUC0-t : 98.16% to 106.35%, AUC0-∞: 98.44% to 108.11%, C max: 99.53% to 104.75%. For d- and l-amphetamine when the tablet has been chewed, T max was 5.00 hours (with a range of 3.00-7.00 hours). PK results were similar for patients in the fasted and fed groups, indicative of no presence of food effect. No serious adverse events (AEs) were reported, overall AE profiles between the tablet and oral suspension were comparable without any unanticipated safety concerns.

Single doses of AMPH ER TAB for both d- and l -amphetamine demonstrated comparable bioavailability to a 20 mg dose of AMPH EROS, 2.5 mg/mL under fasted conditions when chewed and swallowed whole, and demonstrated equivalent peak and overall exposure without apparent food effect. AMPH ER TAB was well-tolerated and consistent with adverse events noted in other amphetamine formulations.

To Investigate the peripheral inflammatory profile in patients with mild cognitive impairment (MCI) from three subgroups – probable Lewy body disease (probable MCI-LB), possible Lewy body disease, and probable Alzheimer’s disease (probable MCI-AD) – as well as associations with clinical features.

Memory clinics and dementia services.

Patients were classified based on clinical symptoms as probable MCI-LB (n = 38), possible MCI-LB (n = 18), and probable MCI-AD (n = 21). Healthy comparison subjects were recruited (n = 20).

Ten cytokines were analyzed from plasma samples: interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-alpha. C-reactive protein levels were investigated.

There was a higher level of IL-10, IL-1beta, IL-2, and IL-4 in MCI groups compared to the healthy comparison group (p < 0.0085). In exploratory analyses to understand these findings, the MC-AD group lower IL-1beta (p = 0.04), IL-2 (p = 0.009), and IL-4 (p = 0.012) were associated with increasing duration of memory symptoms, and in the probable MCI-LB group, lower levels of IL-1beta were associated with worsening motor severity (p = 0.002). In the possible MCI-LB, longer duration of memory symptoms was associated with lower levels of IL-1beta (p = 0.003) and IL-4 (p = 0.026).

There is increased peripheral inflammation in patients with MCI compared to healthy comparison subjects regardless of the MCI subtype. These possible associations with clinical features are consistent with other work showing that inflammation is increased in early disease but require replication. Such findings have importance for timing of putative therapeutic strategies aimed at lowering inflammation.

Befriending by volunteers has the potential to reduce the frequent social isolation of patients with schizophrenia and thus improve health outcomes. However, trial-based evidence for its effectiveness is limited.

To conduct a randomised controlled trial of befriending for patients with schizophrenia or related disorders.

Patients were randomised to a befriending programme for 1 year or to receive information about social activities only (trial registration: ISRCTN14021839). Outcomes were assessed masked to allocation at the end of the programme; at 12 months and at a 6-month follow-up. The primary outcome was daily time spent in activities (using the Time Use Survey (TUS)) with intention-to-treat analysis.

A total of 124 patients were randomised (63 intervention, 61 active control) and 92 (74%) were followed up at 1 year. In the intervention group, 49 (78%) met a volunteer at least once and 31 (49%) had more than 12 meetings. At 1 year, mean TUS scores were more than three times higher in both groups with no significant difference between them (adjusted difference 8.9, 95% CI −40.7 to 58.5, P = 0.72). There were no significant differences in quality of life, symptoms or self-esteem. However, patients in the intervention group had significantly more social contacts than those in the control group at the end of the 12-month period. This difference held true at the follow-up 6 months later.

Although no difference was found on the primary outcome, the findings suggest that befriending may have a lasting effect on increasing social contacts. It may be used more widely to reduce the social isolation of patients with schizophrenia.

To determine the efficacy and safety of amphetamine extended-release oral suspension (AMPH EROS) in the treatment of attention-deficit/hyperactivity disorder (ADHD) compared with placebo in a dose-optimized, randomized, double-blind study.

The efficacy of AMPH EROS was evaluated in a laboratory classroom study conducted in 108 pediatric patients (aged 6–12 years) with ADHD. The study began with an open-label dose optimization (5weeks) with an initial AMPH EROS dose of 2.5 or 5mg once daily in the morning. The dose could be titrated every 4–7 days in increments of 2.5–10mg until an optimal dose or the maximum dose of 20mg/day was reached. Subjects were required to tolerate a minimal dose of 10mg/day. Subjects then entered a 1-week randomized, double-blind treatment phase with the individually optimized dose or placebo. At the end of the week, raters evaluated the attention and behavior of the subjects in a laboratory classroom using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP-C) rating scale. SKAMP-C is a 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting.

The primary efficacy endpoint was change from pre-dose in the SKAMP-C score at 4hours post dose. The key secondary endpoint efficacy parameters were onset and duration of clinical effect. The change scores from pre-dose SKAMP-C scores at post dose time points (1, 2, 6, 8, 10, 12 and 13hours) were used to evaluate the key secondary efficacy endpoints.

More boys (68.7%) than girls participated in the study. The study population was 55.6% white, most patients had inattentive or combined type ADHD presentations. The primary efficacy endpoint, the change from pre-dose SKAMP-C score at 4hours post dose was statistically significantly improved (p<0.0001) compared with placebo. Each of the secondary efficacy endpoints were also significantly improved (p<0.0001 at each time point) compared with placebo. Adverse events reported (frequency >5%) reported during the dose optimization phase were decreased appetite, insomnia, affect lability, upper abdominal pain, mood swings, and headache.

AMPH EROS was effective in reducing symptoms or ADHD from 1 to 13hours after dosing. Adverse events reported were consistent with those of other amphetamine products.

Funding Acknowledgements: This study was supported by Tris Pharma, Inc.

Report the efficacy of open-label amphetamine extended-release oral suspension (AMPH EROS) for the treatment of children with ADHD.

AMPH EROS has a 1-hr onset of effect and a duration of action of 13hours and was approved by FDA for treatment of ADHD in children aged 6–17 years based on a double-blind, placebo-controlled efficacy and safety study in children aged 6–12 years with ADHD. A significant treatment difference in change from pre-dose SKAMP-combined score was observed at the primary endpoint of 4hours post-dose (p<0.0001) and each post-dose time point assessed (1, 2, 4, 6, 8, 10, 12, 13hours).

Data reported here are from the 5-week, open-label dose optimization period. These efficacy data support the primary endpoint result.

Males and females aged 6 to 12 years with ADHD enrolled and began open-label treatment with 2.5 mg or 5mg/day of AMPH EROS titrated in 2.5–10mg/day increments until optimal dose (maximum 20mg/day). Doses could be decreased for tolerability. Subjects took morning AMPH EROS for 5weeks. Other efficacy outcomes during the open-label dose optimization phase: ADHD-RS (ADHD-Rating Scale), CGI-S (Clinical Global Impression of Severity), CGI-I (CGI-of Improvement) and CPRS (Conners’ Parent Rating Scale). All subjects were assessed for safety.

For the ITT population (n=99): treatment with AMPH EROS was associated with a mean change in ADHD-RS-IV (baseline to end of the open-label dose optimization; week 6) of 28.2 (±9.03) (Baseline score = 41.3±7.95). 90.9% of subjects had a change from baseline to open-label week 6 of ≥50% in the ADHD-RS-IV total score and were defined as responders. The CGI-S scores decreased continuously from baseline, with a high 4.8 at baseline to a low of 2.0 at open-label week 6. The percentage of subjects classified as moderately ill or greater correspondingly decreased from 97% at Baseline to 1% at open-label week 6. The decrease in the CGI-I over the study was similar to the change in CGI-S scores. CPRS for most categories decreased continuously from Baseline to open-label week 6. Mean change from baseline to open-label week 6 on the CPRS inattention T-score subscale was –25.3 (±14.38) and –24.4 (±13.87).

Adverse events (>5%) reported during dose optimization were decreased appetite, insomnia, affect lability, upper abdominal pain, mood swings and headache.

AMPH EROS was effective in reducing symptoms of ADHD in this open-label dose optimization. The AE profile of AMPH EROS was consistent with those of other amphetamine products.

Funding Acknowledgements: This work was funded by Tris Pharma, Inc.

To determine whether amphetamine extended-release oralsuspension (AMPH EROS) has an onset of effect at 30minutes postdose inchildren with ADHD.

This randomized, double-blind, 2-treatment, 2-sequence, placebo-controlled crossover pilot study enrolled subjects aged 6 to 12 years withattention-deficit/hyperactivity disorder (ADHD) and ADHD-Rating Scale-5 scores of ≥90th percentile for sex and age. A dose of 5 to 20mg/day of AMPH EROS was determined during a 1-week open-label phase based on medication history, symptom control, and tolerability. Subjects completed a practice laboratory classroom then received one day of double-blind active drug or placebo each in random sequence during 2 double-blind laboratory classroom days. Subjects completed the first double-blind laboratory classroom session, returned to open label drug for 5days then crossed over on day 6 during a second double-blind laboratory classroom session. DB dose was fixed at AMPH EROS 15, 17.5, or 20mg . The primary endpoint was change from predose in the Swanson, Kotkin, Agler, M-Flynn, Pelham rating scale-combined score (SKAMP-C) at 30minutes postdose on two DB days. The key secondary endpoint was change from predose in the SKAMP-C score at 3hours postdose for AMPH EROS compared with placebo. Safety assessments included vital signs and adverse events.

Eighteen subjects were enrolled in the study (14 males and 4 females) with a mean age of 9 years. At both 30minutes and 3hours postdose, changes from baseline in SKAMP-C for AMPH EROS vs. placebo were statistically significant (p<0.01 and p=0.0002, respectively) with corresponding effect sizes of 0.96 and 1.57. Adverse events (>10%) during the open-label phase included upper respiratory tract infection, fatigue, upper abdominal pain, headache, decreased appetite, and affect lability.

AMPH EROS was effective in reducing ADHD symptoms at 30minutes postdose. AEs were mild or moderate and consistent with those of other extended-release amphetamines.

Funding Acknowledgements: Support was provided by Tris Pharma, Inc.