The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

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The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.

Background: Evidence for effective interventions to prevent long-term sequelae after concussion is sparse. This study aimed to test the efficacy of Get going After concussIoN (GAIN), an interdisciplinary, individuallytailored intervention of 8 weeks duration based on gradual return to activities and principles from cognitive behavioural therapy. Methods: We conducted an open-label, parallel-group randomised trial in a hospital setting in Central Denmark Region. Participants were 15À30-year-old patients with high levels of post-concussion symptoms (PCS) 2À6 months post-concussion (i.e., a score 20 on the Rivermead Post-concussion Symptoms Questionnaire (RPQ)). They were randomly assigned (1:1) to either enhanced usual care (EUC) or GAIN+EUC. Masking of participants and therapists was not possible. The primary outcome was change in RPQ-score from baseline to 3-month FU. All analyses were done on an intention-to-treat basis using linear mixed-effects models. This trial is registered with ClinicalTrials.gov, number NCT02337101. Findings: Between March 1, 2015, and September 1, 2017, we included 112 patients. Patients allocated to GAIN+EUC (n=57) reported a significantly larger reduction of PCS than patients allocated to EUC (n=55) with a mean adjusted difference in improvement of 7¢6 points (95% confidence interval (CI) 2¢0À13¢1, p=0¢008), Cohen's d=0¢5 (95% CI 0¢1À0¢9). Number needed to treat for prevention of one additional patient with RPQ 20 at 3-month FU was 3¢6 (95% CI 2¢2À11¢3). No adverse events were observed. Interpretation: Compared with EUC, GAIN+EUC was associated with a larger reduction of post-concussion symptoms at 3-month FU. Funding: Central Denmark Region and the foundation "Public Health in Central Denmark Region-a collaboration between municipalities and the region".

Psychotic experiences are particularly prevalent in the context of affective dysregulation and sleep disturbance, increase with onset of puberty and represent a trans-diagnostic marker of psychopathology.