Innovations In Clinical Neuroscience

JAN-FEB 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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O R I G I N A L R E S E A R C H 30 ICNS Innovations in Clinical Neuroscience • January–February 2018 • Volume 15 • Number 1–2 placed on the dorsal surface of the metatarsal heads and the ankle was placed at 10 degrees of the plantarflexion prior to testing. For each muscle group, the participant was asked to exert maximal force for eight seconds against the dynamometer pad for four trials. The trial in which the most force was exerted (measured in pounds-force) was then used for analyses. This value was averaged for the right and left sides and is referred to hereafter as the "composite dynamometry score." Visit 2 was the baseline visit in which all baseline measures were established prior to treatment. This visit occurred the day before the treatment. The neurologic examination was repeated (by a neurologist who was blind to the results of muscle dynamometry) and the HIV- dementia Motor Score (HDMS) was calculated. 17 The HDMS is a validated instrument that is used to summarize the abnormal neurologic exam findings typical of NeuroAIDS conditions and includes measures of strength, tone, deep tendon reflexes, plantar responses, coordination, and gait and frontal release signs. In addition, we assessed gait with the two minute timed walking test. 18 For Visit 3, the participant was admitted to the Clinical Research Unit (CRU) and assigned a randomization code according to standardized procedures. This code was delivered to and maintained by the Mount Sinai Research Pharmacy. The research pharmacist masked all study drugs by wrapping all tubing and treatment materials in opaque material prior to delivery to the CRU. All study team members interacting with participants were blinded to treatment assignment. Each participant was then infused with either placebo or IVIG (1g/kg) over approximately five hours. To ensure safety, electrocardiogram, vital signs, and adverse event monitoring took place during the infusion and for 90 minutes afterward. Physical examination and appropriate monitoring laboratory tests (CBC and metabolic panel) were also performed on treatment days. Visit 4 occurred the following day and consisted of a second infusion, which was identical to the first. Participants were then evaluated at 14, 28, 42, and 56 days post-infusion (Visits 5–8). These visits were identical and consisted of repetition of the neurological examination and dynamometry. Regulatory considerations . All study procedures were conducted according to a protocol that was approved by the Institutional Review Board of the Icahn School of Medicine at Mount Sinai, in accordance with the ethical principles stated in the United States Title 21 of CFR Parts 50, 54, 56, and 312 and applicable guidelines in Good Clinical Practices (GCP). All members of the research team received appropriate training in the protocol and certification for the Education on the Protection of Human Subjects in Research, the Health Insurance and Portability and Accountability Act of 1996 (HIPAA), and GCP, as required by the United States Food and Drug Administration (FDA) for all research involving human subjects. Additionally, the investigators submitted Forms 1571 and 1572 and the study protocol to the FDA for an investigational new drug (IND) determination. The FDA provided an exemption from the IND regulations for this study. The study was registered with ClinicalTrials.gov (NCT01561755). All participants provided written informed consent. Statistical considerations . In the initial design of the study, both the rarity of HIV- associated myelopathy and the cost of IVIG were taken into account as constraints on the projected sample size. Our goal was to recruit 30 participants (i.e., 15 per treatment group), based on projected feasibility. However, recruitment proved more difficult than anticipated, and we ultimately randomized only 12 participants before determining that attempts at further recruitment were futile (as described further in the Results section). We had originally planned to test the hip flexion composite dynamometry score (HFCDS) as the primary outcome measure using an analysis of covariance (ANCOVA) with Visit 8 (56 days post-infusion) HFCDS as the dependent variable, treatment group as the independent variable, and baseline HFCDS as the covariate. We chose hip flexion because it was deemed the most clinically relevant muscle in terms of walking ability, and dynamometry because it is more quantitative and thus potentially more sensitive to change than other purely clinically based measures, such as the Medical Research Council (MRC) Grading Scale for Strength. However, given the unexpectedly small sample size and the resultant low power to detect between group differences, it was not appropriate to carry out this intended analytic plan. Instead, we limited ourselves to description of the dynamometry and other results for the placebo and IVIG groups over the course of the study, with continuous variables presented as means with standard deviations (SD) or medians with interquartile ranges and categorical variables as frequencies with proportions in descriptive summaries. We had also planned to perform baseline correlational analyses to understand the performance of dynamometry as an outcome measure in this patient population. Despite the smaller than anticipated sample size, these analyses were still possible and included Spearman rank correlations between the CDSs at the screening and baseline visits to assess test-retest reliability and between the CDSs and other validated measures (e.g. HDMS, 2-minute timed walk) to assess validity. Finally, for safety analyses, we described any adverse events experienced by the treatment groups. RESULTS Recruitment and participants . The study was open to enrollment for a total of four years from 2012 to 2016. Nineteen patients provided informed consent to participate, and, of these, 13 were found to be eligible. One participant was lost to follow-up prior to randomization, and 12 participants were randomized and treated. Numerous barriers to recruitment were encountered. Chief among these was the low incidence of new diagnoses of HIVM. Most of the HIVM patients of which we and our referral sources were aware had longstanding disease and had already received IVIG as part of clinical care. While we had originally intended to exclude these patients, we eventually loosened the criteria to allow their participation. However, this did not help significantly, since patients who had found IVIG effective were often still receiving it and were therefore not interested in a placebo-controlled study, and those who had not found IVIG effective saw little purpose in joining the study. Ultimately only one participant who had previously received IVIG was enrolled; this participant was randomized to the placebo group. Of the 12 participants enrolled, all were successfully randomized, six to IVIG and six to placebo, and all were treated. One member of the IVIG group attended only one assessment following treatment (Visit 6, ~28 days after treatment), and so this participant's data were included only in the safety analyses. The 11 remaining participants attended all subsequent

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