Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis.

BACKGROUND: Autologous mesenchymal stem cell neurotrophic factor-secreting cells (NurOwn®) have the potential to modify underlying disease mechanisms in progressive multiple sclerosis (PMS). OBJECTIVE: This open-label phase II study was conducted to evaluate safety/efficacy of three intrathecal cell treatments. METHODS: Eighteen participants with non-relapsing PMS were treated. The primary endpoint was safety. Secondary endpoints included: cerebrospinal fluid (CSF) biomarkers; timed 25-foot walk speed, nine-hole peg test (9-HPT), low-contrast letter acuity, symbol digit modalities test, and 12-item multiple sclerosis (MS) walking scale. Seventeen participants received all treatments. RESULTS: No deaths/adverse events related to worsening of MS, clinical/magnetic resonance imaging (MRI) evidence of disease activation, and clinically significant changes in safety lab results were reported. Two participants developed symptoms of low back and leg pain, consistent with a diagnosis of arachnoiditis, occurring in one of three intrathecal treatments in both participants. Nineteen percent of treated participants achieved pre-specified ⩾ 25% improvements in timed 25-foot walk speed/nine-HPT at 28 weeks compared to baseline, along with consistent efficacy signals for pre-specified response criteria across other secondary efficacy outcomes. CSF neuroprotective factors increased, and inflammatory biomarkers decreased after treatment, consistent with the proposed mechanism of action. CONCLUSION: Based on these encouraging preliminary findings, further confirmation in a randomized study is warranted.

Spontaneous Motor Recovery after Cervical Spinal Cord Injury: Issues for Nerve Transfer Surgery Decision Making.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To quantify spontaneous upper extremity motor recovery between 6 and 12 months after spinal cord injury (SCI) to help guide timing of nerve transfer surgery to improve upper limb function in cervical SCI. SETTING: Nineteen European SCI rehabilitation centers. METHODS: Data was extracted from the European Multicenter Study of SCI database for individuals with mid-level cervical SCI (N = 268). Muscle function grades at 6 and 12 months post-SCI were categorized for analysis. RESULTS: From 6 to 12 months after SCI, spontaneous surgically-relevant recovery was limited. Of all limbs (N = 263) with grade 0-2 elbow extension at 6 months, 4% regained grade 4-5 and 11% regained grade 3 muscle function at 12 months. Of all limbs (N = 380) with grade 0-2 finger flexion at 6 months, 3% regained grade 4-5 and 5% regained grade 3 muscle function at 12 months. CONCLUSION: This information supports early (6 month) post-injury surgical consultation and evaluation. With this information, individuals with SCI can more fully engage in preference-based decision-making about surgical intervention versus continued rehabilitation and spontaneous recovery to gain elbow extension and/or hand opening and closing.

Evaluation of Functional Independence in Cervical Spinal Cord Injury: Implications for Surgery to Restore Upper Limb Function.

PURPOSE: To help individuals make informed choices regarding the optimal type and timing of restorative surgical treatment for cervical spinal cord injury (SCI), more precise information is needed on their ability to perform activities of daily living. The goal of this work was to describe functional independence achieved by individuals with differing levels of cervical SCI. METHODS: Using the comprehensive European Multicenter Study of Spinal Cord Injury dataset, analysis was undertaken of individuals with traumatic SCI, motor-level C5-C8. Data on feeding, bladder management, and transfers (bed to wheelchair) were compared between individuals with different levels of injury. Subgroup analyses of symmetrical and asymmetrical SCI and between complete and incomplete SCI were performed. The impact of age, sex, and time postinjury on functional independence was ascertained. RESULTS: Data were available for individuals with symmetrical (n = 204) and asymmetrical (n = 95) patterns of SCI. Independence with feeding, urinary function, and transfer ability was increased in individuals with strong finger flexion. Unexpectedly, the presence of strong elbow extension did not uniformly result in the ability to transfer independently. There was no change in any of the analyzed activities between 6 and 12 months postinjury. CONCLUSIONS: People with cervical SCI who gain finger flexion have greater independence with feeding, urinary, and transfer activities. Restoration of finger flexion should be a reconstructive priority for individuals with midcervical-level SCI. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results.

OBJECTIVE: To determine the safety and efficacy of mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells (NurOwn®, autologous bone marrow-derived MSCs, induced to secrete NTFs) delivered by combined intrathecal and intramuscular administration to participants with amyotrophic lateral sclerosis (ALS) in a phase 2 randomized controlled trial. METHODS: The study enrolled 48 participants randomized 3:1 (treatment: placebo). After a 3-month pretransplant period, participants received 1 dose of MSC-NTF cells (n = 36) or placebo (n = 12) and were followed for 6 months. CSF was collected before and 2 weeks after transplantation. RESULTS: The study met its primary safety endpoint. The rate of disease progression (Revised ALS Functional Rating Scale [ALSFRS-R] slope change) in the overall study population was similar in treated and placebo participants. In a prespecified rapid progressor subgroup (n = 21), rate of disease progression was improved at early time points (p < 0.05). To address heterogeneity, a responder analysis showed that a higher proportion of treated participants experienced ≥1.5 points/month ALSFRS-R slope improvement compared to placebo at all time points, and was significant in rapid progressors at 4 and 12 weeks (p = 0.004 and 0.046, respectively). CSF neurotrophic factors increased and CSF inflammatory biomarkers decreased in treated participants (p < 0.05) post-transplantation. CSF monocyte chemoattractant protein-1 levels correlated with ALSFRS-R slope improvement up to 24 weeks (p < 0.05). CONCLUSION: A single-dose transplantation of MSC-NTF cells is safe and demonstrated early promising signs of efficacy. This establishes a clear path forward for a multidose randomized clinical trial of intrathecal autologous MSC-NTF cell transplantation in ALS. CLASSIFICATION OF EVIDENCE: This phase II study provides Class I evidence.

Comorbidities, Concomitant Medications, and Diet as Factors Affecting Levothyroxine Therapy: Results of the CONTROL Surveillance Project.

BACKGROUND: The CONTROL Surveillance Project was a comprehensive patient-based survey conducted among hypothyroid patients undergoing treatment. The primary objective of the study was to specifically quantify the prevalence of factors adversely affecting levothyroxine therapy. METHODS: Participants were selected from a large proprietary database. Those eligible for the study completed a 21-question survey. RESULTS: Of the eligible hypothyroid patients, 925 (92.5%) were being treated with levothyroxine monotherapy. The mean age was 60.4 years; 755 (81.6%) were female and 168 (18.2%) were male. Almost half of those receiving levothyroxine (435, 47.0%) had at least one comorbid condition that could adversely affect its absorption: gastroesophageal reflux disease (33.8% of patients), irritable bowel syndrome (9.7%), lactose intolerance (7.8%), or a history of gastric bypass surgery or bowel resection (3.0%). Other factors reported by many patients that could adversely affect levothyroxine absorption included use of prescription medications (20.6%) and over-the-counter medications (34.3%) used to treat comorbid gastrointestinal (GI) conditions; use of dietary supplements (51.8%, primarily calcium and iron); and intake of foods/beverages high in fiber, iodine, or soy (68.0%). Of the 13.4% who reported difficulty controlling their hypothyroid symptoms, significantly more patients with comorbid GI conditions reported such difficulty (7.8 versus 5.6%, P < 0.01). Frequent changes in levothyroxine dosing (two or more dose changes in the past year) were reported by 8.0% of survey participants. Those with GI comorbidities were nearly twice as likely to have such changes (5.0 versus 3.0%, P < 0.01). CONCLUSION: Better initial workup of patients, including identification of relevant GI comorbidities and allergies, may help in the early detection of factors that may affect the performance of levothyroxine.