Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study.

BACKGROUND: Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. OBJECTIVE: This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. METHODS: This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. RESULTS: Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection. CONCLUSION: PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose.

Comparative injection-site pain and tolerability of subcutaneous serum-free formulation of interferonß-1a versus subcutaneous interferonß-1b: results of the randomized, multicenter, Phase IIIb REFORMS study.

BACKGROUND: In patients with relapsing-remitting multiple sclerosis (RRMS), subcutaneous (sc) interferon (IFN)ß-1a and IFNß-1b have been shown to reduce relapse rates. A formulation of IFNß-1a has been produced without fetal bovine serum and without human serum albumin as an excipient (not currently approved for use in the US). The objectives of this study were to evaluate tolerability, injection-site redness, subject-reported satisfaction with therapy, and clinical safety and efficacy of the serum-free formulation of IFNß-1a versus IFNß-1b in IFNß-treatment-naïve patients with RRMS. The objectives of the extension phase were to evaluate long-term safety and tolerability of IFNß-1a. METHODS: This randomized, parallel-group, open-label study was conducted at 27 clinical sites in the US. Eligible patients aged 18-60 years were randomized to receive either IFNß-1a, titrated to 44 µg sc three times weekly (tiw) (n = 65), or IFNß-1b, titrated to 250 µg sc every other day (n = 64) over 12 weeks. Following this, all patients received IFNß-1a 44 µg tiw for 82-112 weeks. Primary endpoint was mean change in patient-reported pain, as assessed by visual analog scale (VAS) diary pain score (from 0 mm [no pain] to 100 mm [worst possible pain]) at the injection site, from pre-injection to 30 min post-injection over the first 21 full-dose injections. Secondary assessments included proportion of patients pain-free as recorded by VAS diary and the Short-Form McGill Pain questionnaire VAS. RESULTS: A total of 129 patients were included in the intent-to-treat analysis. Mean (standard deviation) change in VAS diary pain score was not significantly different between groups, although numerically lower with IFNß-1a versus IFNß-1b from pre-injection to immediately post-injection (1.46 [2.93] vs. 4.63 [10.57] mm), 10 min post-injection (0.70 [1.89] vs. 1.89 [5.75] mm), and 30 min post-injection (0.67 [2.32] vs. 1.14 [4.94] mm). Proportion of patients pain-free at all time periods post-injection was also not significantly different between groups. Adverse events were consistent with the known safety profiles of these treatments. CONCLUSIONS: In IFNß-treatment-naïve patients with RRMS, both the serum-free formulation of IFNß-1a and IFNß-1b treatments were generally accompanied by low-level injection-site pain and were well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00428584.

Effect of vicriviroc on the QT/corrected QT interval and central nervous system in healthy subjects.

Vicriviroc is a CCR5 antagonist in clinical development for the treatment of HIV-1. Two phase I studies were conducted to assess the safety of vicriviroc. One study characterized the drug's potential to prolong the QT/corrected QT (QTc) interval and to induce arrhythmia. In this partially blind, parallel-group study, 200 healthy subjects aged 18 to 50 years were randomized in equal groups to the following regimens: (i) placebo for 9 days and a single dose of moxifloxacin at 400 mg on day 10, (ii) placebo, (iii) vicriviroc-ritonavir (30 and 100 mg), (iv) vicriviroc-ritonavir (150 and 100 mg), and (v) ritonavir (100 mg). The second study characterized the effects of a range of vicriviroc doses on the central nervous system (CNS). In this third-party-blind, parallel-group study, 30 healthy subjects aged 18 to 48 years were randomized to receive a single dose of either vicriviroc at 200, 250, or 300 mg or placebo, followed by multiple (seven) once-daily doses of either vicriviroc at 150, 200, or 250 mg or placebo, respectively. In the first study, vicriviroc produced no clinically meaningful effect on the QT/QTc interval when administered at a supratherapeutic or therapeutic dose concurrently with ritonavir. In the second study, vicriviroc produced no observable seizure activity, nor was it held to be associated with any clinically relevant changes in brain waveforms in the final consensus of reviewers. These findings showed that vicriviroc produced no clinically relevant QTc prolongation cardiac or epileptogenic effects in healthy individuals at exposures as high as five times those expected for HIV-infected patients receiving therapeutic doses of vicriviroc in a ritonavir-boosted protease inhibitor-containing regimen.

The relationship between manual handling performance and recent flying experience in air transport pilots.

Modern jet transport aircraft are typically flown using the on-board automation by the pilot programming commands into the auto-flight systems. Anecdotal evidence exists suggesting that pilots of highly automated aircraft experience manual flying skills decay as a result of a lack of opportunity to practise hand-flying during line operations. The ability of a pilot to revert to basic manual control is essential, for example, in cases where the aircraft's automatic capability is diminished or when reconfiguring the automatics is an ineffective use of crew capacity. However, there is a paucity of objective data to substantiate this perceived threat to flight safety. Furthermore, traditional performance measurement techniques may lack the ability to identify subtle but significant differences in pilots' manual handling ability in large transport aircraft. This study examines the relationship between pilot manual handling performance and their recent flying experience using both traditional flight path tracking measures and frequency-based control strategy measures. Significant relationships are identified between pilots' very recent flying experience and their manual control strategy. Statement of Relevance: The study demonstrates a novel application of frequency analysis, which produces a broader and more sensitive analysis of pilot performance than has been offered in previous research. Additionally, the relationships that are found to exist between recent flying experience and manual flying performance will help to guide future pilot assessment and training.

Combining control input with flight path data to evaluate pilot performance in transport aircraft.

INTRODUCTION: When deriving an objective assessment of piloting performance from flight data records, it is common to employ metrics which purely evaluate errors in flight path parameters. The adequacy of pilot performance is evaluated from the flight path of the aircraft. However, in large jet transport aircraft these measures may be insensitive and require supplementing with frequency-based measures of control input parameters. METHOD: Flight path and control input data were collected from pilots undertaking a jet transport aircraft conversion course during a series of symmetric and asymmetric approaches in a flight simulator. The flight path data were analyzed for deviations around the optimum flight path while flying an instrument landing approach. Manipulation of the flight controls was subject to analysis using a series of power spectral density measures. RESULTS: The flight path metrics showed no significant differences in performance between the symmetric and asymmetric approaches. However, control input frequency domain measures revealed that the pilots employed highly different control strategies in the pitch and yaw axes. CONCLUSION: The results demonstrate that to evaluate pilot performance fully in large aircraft, it is necessary to employ performance metrics targeted at both the outer control loop (flight path) and the inner control loop (flight control) parameters in parallel, evaluating both the product and process of a pilot's performance.