To add or not to add a new treatment arm to a multiarm study: A decision-theoretic framework.

Multiarm clinical trials, which compare several experimental treatments against control, are frequently recommended due to their efficiency gain. In practise, all potential treatments may not be ready to be tested in a phase II/III trial at the same time. It has become appealing to allow new treatment arms to be added into on-going clinical trials using a "platform" trial approach. To the best of our knowledge, many aspects of when to add arms to an existing trial have not been explored in the literature. Most works on adding arm(s) assume that a new arm is opened whenever a new treatment becomes available. This strategy may prolong the overall duration of a study or cause reduction in marginal power for each hypothesis if the adaptation is not well accommodated. Within a two-stage trial setting, we propose a decision-theoretic framework to investigate when to add or not to add a new treatment arm based on the observed stage one treatment responses. To account for different prospect of multiarm studies, we define utility in two different ways; one for a trial that aims to maximise the number of rejected hypotheses; the other for a trial that would declare a success when at least one hypothesis is rejected from the study. Our framework shows that it is not always optimal to add a new treatment arm to an existing trial. We illustrate a case study by considering a completed trial on knee osteoarthritis

Utility of the heated lidocaine/tetracaine patch in the treatment of pain associated with shoulder impingement syndrome: a pilot study

Richard Radnovich,1 Thomas B Marriott21Injury Care Medical Center, Boise, ID, USA; 2Pain Group, Nuvo Research US, Salt Lake City, UT, USAIntroduction: Pain control is an important first step in the treatment of shoulder impingement syndrome (SIS) because fear of pain must be removed as an obstacle to participation in an appropriate physical therapy program.Methods: Adult patients with SIS-associated pain of at least 2 weeks’ duration and who had an average pain score of ≥4 on the zero- to ten-point Numeric Pain Rating Scale were eligible to enroll in this 2-week pilot study. Patients were treated with the heated lidocaine/tetracaine (70 mg/70 mg) patch (HLT patch) placed over the site of shoulder tenderness each morning and evening for a period of 2 to 4 hours. Average and worst pain during the previous 24 hours and shoulder range of motion were assessed at baseline and on Day 14. Results were expressed as change and percent change from baseline to Day 14. This pilot study was not powered for rigorous statistical analysis.Results: Twenty patients (seven male, 13 female; average age 51.2 ± 10.8 years [mean ± standard deviation]) enrolled in this study, and 18 patients completed the protocol. The mean average pain score at baseline was 5.5 ± 1.1 (range 4 to 8). In the per-protocol population, average and worst pain scores declined by 2.4 ± 2.0 and 3.7 ± 2.7 points, respectively. Two-thirds of the patients demonstrated a clinically meaningful ≥30% decline in average pain score, and half of the patients demonstrated a ≥50% decline in average pain score. Shoulder internal rotation increased by 29.7° ± 21.8° and abduction increased by 40.0° ± 44.2°. Application-site erythema was reported by ten patients at some time during the study.Conclusion: Patients treated with the HLT patch for 14 days demonstrated clinically meaningful improvement in pain intensity and range of motion. Further controlled research is necessary to characterize the efficacy and tolerability of the HLT patch in the treatment of SIS.Keywords: SIS, HLT patch, range of motion, pain intensit

A randomized clinical study of the heated lidocaine/tetracaine patch versus subacromial corticosteroid injection for the treatment of pain associated with shoulder impingement syndrome

Richard Radnovich,1 Jeremiah Trudeau,2 Arnold R Gammaitoni3 1Injury Care Medical Center, Boise, ID, USA; 2Analgesic Solutions, Natick, MA, USA; 3Nuvo Research Inc., West Chester, PA, USA Background: Treatment for pain due to shoulder impingement syndrome (SIS) typically begins conservatively with nonsteroidal anti-inflammatory drugs and physical therapy and can include subacromial injection of corticosteroids, particularly in patients unresponsive to conservative measures. The heated lidocaine/tetracaine (HLT) patch has been reported to reduce SIS pain in a small case series. Methods: This was a prospective, randomized, open-label clinical trial in which adult patients with SIS pain lasting at least 14 days, with an average intensity of ≥4 on a 0–10 scale (0= no pain, 10= worst pain) were randomized to treatment with the HLT patch or a single subacromial injection of triamcinolone acetonide (10 mg). Patients in the HLT patch group applied a single HLT patch to the shoulder for 4 hours twice daily, with a 12-hour interval between treatments during the first 14 days, and could continue to use the patch on an as-needed basis (up to twice daily) during the second 14-day period. No treatment was allowed in the final 14-day period. At baseline and at days 14, 28, and 42, patients rated their pain and pain interference with specific activities (0–10 scale). Results: Sixty patients enrolled in the study (average age =51 years, range 18–75, n=21 female). Average pain scores declined from 6.0±1.6 at baseline to 3.5±2.4 at day 42 in the HLT patch group (n=29, P<0.001) and from 5.6±1.2 to 3.2±2.6 in the injection group (n=31, P<0.001). Similar improvements were seen in each group for worst pain; pain interference with general activity, work, or sleep; and range of motion. No significant between-group differences were seen for any pain or pain interference scores at any time point. Conclusion: These results suggest that short-term, noninvasive treatment with the HLT patch has similar efficacy to subacromial corticosteroid injections for the treatment of pain associated with SIS. Keywords: shoulder impingement syndrome, corticosteroids, heated lidocaine/tetracaine patch, pai

Affect recognition, empathy, and dysosmia after traumatic brain injury

Zupan, BA ORCiD: 0000-0002-4603-333XObjective: To investigate if olfaction is associated with affect recognition and empathy deficits after traumatic brain injury (TBI). Prior research has shown that TBI often leads to loss of smell. We hypothesized a relationship with emotion perception, because the neural substrates of the olfactory system overlap with the ventral circuitry of the orbital frontal cortex, which play a critical role in affective responses, such as empathy. Design: Comparative study investigating differences between participants with TBI who had impaired olfaction (dysosmia) with those with normal olfaction (normosmia). Setting: Postacute rehabilitation facilities in the United States, Canada, and New Zealand. Participants: Participants (N=106) in the current study were a convenience sample of adults with moderate to severe TBI who were tested for olfactory function as part of a larger, related study on affect recognition. On average, participants were 11.5 years postinjury. Interventions: Not applicable. Main Outcome Measures: Olfaction (Brief Smell Identification Test), facial affect recognition (Diagnostic Assessment of Nonverbal Affect 2-Adult Faces [DANVA2-AF]), vocal affect recognition (Diagnostic Assessment of Nonverbal Affect 2-Adult Paralanguage [DANVA2-AP] ), emotional inference (Emotional Inference from Stories Test [EIST]), and empathy (Interpersonal Reactivity Index [IRI] ). Results: Fifty-six percent of participants were dysosmic and only 36% of these participants were aware of their deficit. Participants with dysosmia performed significantly poorer on the DANVA2-AF (P=.003), DANVA2-AP (P=.007), EIST (P=.016), and IRI (P=.013). Medium effect sizes were found for all measures. Dysosmia had a sensitivity value of 86.4% for detecting facial affect recognition impairments and 67.8% for vocal affect recognition impairments. Conclusions: This study shows that olfactory deficits may be indicative of affect recognition impairments and reduced empathy. Early knowledge of affect recognition and empathy deficits would be valuable so that treatment could be implemented predischarge. © 2012 American Congress of Rehabilitation Medicine

Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial.

ObjectiveEvaluate the efficacy and safety/tolerability of cryoneurolysis for reduction of pain and symptoms associated with knee osteoarthritis (OA).DesignRandomized, double-blind, sham-controlled, multicenter trial with a 6-month follow-up in patients with mild-to-moderate knee OA. Patients were randomized 2:1 to cryoneurolysis targeting the infrapatellar branch of the saphenous nerve (IPBSN) or sham treatment. The primary endpoint was the change from baseline to Day 30 in the Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain score adjusted by the baseline score and site. Secondary endpoints, including visual analogue scale (VAS) pain score and total WOMAC score, were tested in a pre-defined order.ResultsThe intent-to-treat (ITT) population consisted of 180 patients (n = 121 active treatment, n = 59 sham treatment). Compared to the sham group, patients who received active treatment had a statistically significant greater change from baseline in the WOMAC pain subscale score at Day 30 (P = 0.0004), Day 60 (P = 0.0176), and Day 90 (P = 0.0061). Patients deemed WOMAC pain responders at Day 120 continued to experience a statistically significant treatment effect at Day 150. Most expected side effects were mild in severity and resolved within 30 days. The incidence of device- or procedure-related adverse events was similar in the two treatment groups with no occurrence of serious or unanticipated adverse device effects (ADE).ConclusionsCryoneurolysis of the IPBSN resulted in statistically significant decreased knee pain and improved symptoms compared to sham treatment for up to 150 days, and appeared safe and well tolerated

Novel cryoneurolysis device for the treatment of sensory and motor peripheral nerves

IntroductionCryoneurolysis is the direct application of low temperatures to reversibly ablate peripheral nerves to provide pain relief. Recent development of a handheld cryoneurolysis device with small gauge probes and an integrated skin warmer broadens the clinical applications to include treatment of superficial nerves, further enabling treatments for pre-operative pain, post-surgical pain, chronic pain, and muscle movement disorders.Areas coveredCryoneurolysis is the direct application of cold temperatures to a peripheral nerve, resulting in reversible ablation due to Wallerian degeneration and nerve regeneration. Use over the last 50 years attests to a very low incidence of complications and adverse effects. Cryoprobes have traditionally been applied through a surgical incision; but, recent technical advances allow percutaneous administration. A new hand-held device is now approved for use within the United States. Cryoneurolysis has been used to treat postoperative and chronic pain states as well as spasticity. Expert commentary: Changes in the US healthcare system such as a push for the reduction of opioid use and the incorporation of Diagnostic Related Group codes, as well as recent technological advances including a handheld unit that allows for treatment of superficial nerves while protecting the skin from damage, may contribute to the resurgence of cryoneurolysis for the treatment of peripheral nerves