An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

Background/Aims: Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible. Methods: In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study. Results: All healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll. Conclusions: A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided. Keywords: Social media, Altruism, Spinal muscle atrophy, Healthy controls, Network

BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (<= 100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P = 0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression.

Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible.In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study.All healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll.A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided.

BACKGROUND/AIMS:Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible.METHODS:In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study.RESULTS:All healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll.CONCLUSIONS:A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided.

Background/Aims: Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible. Methods: In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study. Results: All healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll. Conclusions: A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided.

OBJECTIVE:Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.METHODS:A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed.RESULTS:Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17).INTERPRETATION:These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891.

Objective: To characterize the primary progressive (PPMS) and secondary progressive (SPMS) MS subjects enrolled in a Phase II clinical trial. Background: There is growing evidence that PPMS and SPMS are more similar than different. Differences among subjects with these forms of MS enrolling into clinical trials are not well understood, but may have a significant impact on the outcome of trials. Design/Methods: NN 102/SPRINT-MS is a phase II trial of ibudilast in primary and secondary progressive MS utilizing the NINDS-sponsored NeuroNEXT clinical trial network. Subjects were enrolled at 28 US sites, randomized 1:1 to ibudilast 100mg/d or placebo, and are being followed over 96 weeks. Enrollment was open to both PPMS and SPMS patients, with the same inclusion and exclusion criteria applied to both groups. Two sample t-tests were used to compare the means of clinical and imaging variables. Results: Of 314 enrolled subjects, there were 261 unique subjects with sufficient clinical and imaging data at screening for inclusion in this analysis. There was no difference in age (SPMS 55.8y, PPMS 55.2y), 9-hole peg test time (SPMS 36.9s, PPMS 32.9s), or Symbol Digit Modality Test score (SPMS 43.4, PPMS 40.4) (all p>0.05). However, SPMS had longer disease duration (16.2y vs 7.8y PPMS; p Conclusions: Despite identical inclusion and exclusion criteria, PPMS and SPMS subjects enrolling into the same clinical trial had different clinical and imaging disease characteristics. These differences may have a significant impact on the results of the clinical trial and should be considered when analyzing the results of studies that enroll both disease types. Study Supported by: Support by National Institute of Health (U01NS082329), NeuroNEXT Network (Central Coordinating Center: U01NS077179; Data Coordinating Center: U01NS077352), National Multiple Sclerosis Society (RG-5184-A-6) and Medicinova Disclosure: Dr. Fox has received personal compensation for activities with Actelion, Biogen, Genentech, Mallinckrodt, MedDay, Novartis, and Teva Neuroscience as a consultant. Dr. Fox has received research support from Novartis. Dr. Ashokkumar has nothing to disclose. Dr. Coffey has received consulting fees from ZZ Biotech, LLC.,,,,,, Dr. Conwit has nothing to disclose. Dr. Cudkowicz has received personal compensation for activities with Cytokinetics, Lilly, Astra Zenica, Biohaven, Genentech. Jama Neurology. Dr. Ecklund has nothing to disclose. Dr. Gleason has nothing to disclose. Dr. Goodman received personal compensation for activities with Abbvie, Acorda Therapeutics, Atara, Bayer HealthCare, Biogen, Novartis, Sanofi-Genzyme, and Teva. Dr. Goodman has received research support from Acorda, Avanir, Biogen, EMD-Serono, Novartis, Ono, Roche, Sanofi-Genzyme, Sun and Teva. Dr. Klawiter has received personal compensation for activities with Atlas5d, Biogen Idec, EMD Serono, Genentech, and Shire as a consultant. Dr. Klawiter has received research support for clinical research projects and clinical trials from Atlas5d, Biogen, EMD Serono, and Roche.. Dr. Koepp has nothing to disclose. Dr. Matsuda has received personal compensation for activities with MediciNova. Dr. McGovern has nothing to disclose. Dr. Naismith has received personal compensation for activities with Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genyzme, Novartis, and Teva. Dr. Naismith has received research support from Alkermes. Dr. Natarajan has nothing to disclose. Dr. Thornell has nothing to disclose. Dr. Yankey has nothing to disclose.

OBJECTIVE:This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA).METHODS:This prospective, multi-center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits.RESULTS:Enrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography (EIM) high-frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts.INTERPRETATION:By the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit.

BACKGROUND:Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials.METHODS:SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening.RESULTS:A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017.CONCLUSION:SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

OBJECTIVE: To report baseline characteristics of subjects enrolled in a phase II trial of ibudilast in progressive MS (PMS). BACKGROUND: Approved therapies for relapsing remitting MS lack proven efficacy in PMS. The optimal outcome metric for phase II trials in PMS is unknown. Ideally, a phase II trial in PMS would both evaluate a potential therapy and establish outcome metrics. DESIGN/METHODS: NN 102/SPRINT-MS is a phase II trial of ibudilast in primary and secondary PMS utilizing the NINDS-sponsored NeuroNEXT clinical trial network. The trial will evaluate the safety, tolerability, and activity of ibudilast and directly compare imaging outcome metrics: whole brain atrophy, magnetization transfer imaging, diffusion tensor imaging, optical coherence tomography, and cortical atrophy. Approximately 250 subjects will be randomized at 28 US sites, randomized 1:1 to ibudilast 100mg/d or placebo, and followed over 96 weeks. RESULTS: As of October 2014, 225 subjects were enrolled and 164 randomized. Of those randomized, mean age = 55.7 yrs (SD 7.3; range 31-65); 54[percnt] female; 93[percnt] white; 4.3[percnt] Latino; mean EDSS = 5.40 (SD 1.1; range 3 - 7), mean 25FW time = 16.1 seconds (SD 19.4; range 4.05 - 180), and mean 9HPT time = 32.9 seconds (SD 16.5; range 16.3 - 111.3) (dominant) and 42.3 seconds (SD 46.3; range 17.5 - 300) (non-dominant). Enrollment is projected to be completed by January 2015. Baseline characteristics of the fully-enrolled study will be presented. CONCLUSIONS: The NN102/SPRINT-MS will evaluate the activity of ibudilast and directly compare five imaging outcome metrics to help improve the conduct of phase II trials in PMS. To date, baseline characteristics are typical of the PMS population. Study Supported by: Support by National Institute of Health (U01NS082329), National Multiple Sclerosis Society (RG-5184-A-6) and Medicinova