A Phase II Randomized, Double-Blind, Placebo-Controlled Safety and Efficacy Study of Lenalidomide in Lumbar Radicular Pain with a Long-Term Open-Label Extension Phase.

OBJECTIVE: This phase II study assessed lenalidomide efficacy and safety. DESIGN: Three-phase core study: 14-day prerandomization, 12-week treatment, and 52-week open-label extension. SETTING: Fourteen US centers from July 2005 to July 2007. SUBJECTS: Chronic lumbar radicular pain patients without history of nerve injury or deficit. METHODS: Subjects were randomized (1:1) to double-blind treatment with lenalidomide 10 mg or placebo once daily for 12 weeks, followed by a 52-week open-label extension. A 12-week, single-center, randomized-withdrawal (1:2, lenalidomide:placebo), exploratory study with open-label extension was undertaken in 12 subjects from the core extension who were naïve to neuropathic medications and with at least a two-point decrease from baseline average daily Pain Intensity-Numerical Rating Scale score. RESULTS: Of 180 subjects enrolled, 176 had at least one postbaseline measure; 132 completed the 12-week treatment phase. In the core study, no statistically significant difference in Pain Intensity-Numerical Rating Scale mean change (-0.02, P = 0.958) was observed at week 12 between lenalidomide and placebo; proportions achieving pain reduction at week 12 and other secondary measures were comparable between lenalidomide and placebo. In the exploratory study, week 12 mean changes in Pain Intensity-Numerical Rating Scale scores were -0.05 (lenalidomide: N = 3) and 2.11 (placebo: N = 8). Mean changes in Brief Pain Inventory-short form interference scores were -3.33 and 8.38, respectively; scores at six months were maintained or decreased in 10 of 12 subjects. CONCLUSIONS: While this study does not support lenalidomide use in an unselected lumbar radicular pain population, an immunomodulating agent may relieve pain in select subjects naïve to neuropathic pain medications.ClinicalTrials.gov identifier: NCT00120120

Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model

Objectives: Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB).We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. Methods: A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with orwithout CC-11050, starting at fourweeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. Results: Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050- treated, compared to the untreated rabbits. Conclusions: Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment.We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment

A Double-Blind, Placebo-Controlled Withdrawal Trial of Dexmethylphenidate Hydrochloride in Children with Attention Deficit Hyperactivity Disorder

Objectives: d,l-threo-methylphenidate HCl (d,l-MPH) is the most common treatment of attention deficit hyperactivity disorder (ADHD). A previous report showed placebo-controlled efficacy for the purified disomer (dexmethylphenidate hydrochloride, d-MPH, Focalin™) with a 2:1 potency compared to dl, and suggested a 6-hour duration of action. This study complements that report by studying the effect of placebo-controlled discontinuation and retesting the duration of action. Methods: A 6-week, open-label titration of d-MPH (2.5–10 mg twice-a-day) was followed by a doubleblind, placebo-controlled, 2-week withdrawal study of responders. Results: In the open titration, 82% of the 89 enrolled patients achieved a Clinical Global Impression— Improvement (CGI-I) rating of much or very much improved. Only 5 patients discontinued for adverse events. Seventy-five patients continued into the placebo-controlled discontinuation. For the randomly assigned d-MPH (n = 35) and placebo (n = 40) groups, mean ages, respectively, were 10.1 ± 2.9 and 9.9 ± 2.7 years, 86% and 78% were male, and 70.6% and 80.0% took the ceiling dose of 10 mg twice-daily, respectively. Each group had 80% combined-type ADHD and 20% inattentive type. By the end of the 2- week, placebo-masked withdrawal, significantly more placebo patients (24 of 39) than d-MPH continuers (6 of 35) relapsed (61.5% versus 17.1%, p = 0.001). Compared to d-MPH continuers, placebo patients deteriorated significantly more in the 2-week period on teacher ratings of the 18 ADHD symptoms rated 0– 3 (p = 0.028), the 3 p.m. and 6 p.m. parent ADHD symptom ratings (p = 0.0026 and p = 0.0381, respectively), and clinic (2–3 p.m.) and home (6 p.m.) Math Tests (p = 0.024 and p < 0.0001, respectively). The 6 p.m. scores replicated the significant effect at 6 hours reported in the previous study. Conclusions: d-MPH is safe, tolerable, and effective, with a 6-hour duration of effect suggested by the significant difference from placebo at 6 hours on a double-blind discontinuation

Pharmacologic inhibition of host Phosphodiesterase-4 improves isoniazid-Mediated clearance of Mycobacterium tuberculosis

The lengthy duration of multidrug therapy needed to cure tuberculosis (TB) poses significant challenges for global control of the disease. Moreover, chronic inflammation associated with TB leads to pulmonary damage that can remain even after successful cure. Thus, there is a great need for the development of effective shorter drug regimens to improve clinical outcome and strengthen TB control. Host-directed therapy (HDT) is emerging as a novel adjunctive strategy to enhance the efficacy and shorten the duration of TB treatment. Previously, we showed that the administration of CC-3052, a phosphodiesterase-4 inhibitor (PDE4i), reduced the host inflammatory response during Mycobacterium tuberculosis (Mtb) infection and improved the antimicrobial efficacy of isoniazid (INH) in both the mouse and rabbit models. In the present study, we evaluated the pharmacokinetics and explored the mechanism underlying the efficacy of a more potent PDE4i, CC-11050, as adjunct to INH treatment in a mouse model of pulmonary Mtb infection. Genome-wide lung transcriptome analysis confirmed the dampening of inflammation and associated network genes that we previously reported with CC-3052. Consistent with the reduction in inflammation, a significant improvement in Mtb control and pathology was observed in the lungs of mice treated with CC-11050 plus INH, compared to INH alone. This important confirmatory study will be used to help design upcoming human clinical trials with CC-11050 as an HDT for TB treatment

Pharmacologic inhibition of host Phosphodiesterase-4 improves isoniazid-Mediated clearance of Mycobacterium tuberculosis

The lengthy duration of multidrug therapy needed to cure tuberculosis (TB) poses significant challenges for global control of the disease. Moreover, chronic inflammation associated with TB leads to pulmonary damage that can remain even after successful cure. Thus, there is a great need for the development of effective shorter drug regimens to improve clinical outcome and strengthen TB control. Host-directed therapy (HDT) is emerging as a novel adjunctive strategy to enhance the efficacy and shorten the duration of TB treatment. Previously, we showed that the administration of CC-3052, a phosphodiesterase-4 inhibitor (PDE4i), reduced the host inflammatory response during Mycobacterium tuberculosis (Mtb) infection and improved the antimicrobial efficacy of isoniazid (INH) in both the mouse and rabbit models. In the present study, we evaluated the pharmacokinetics and explored the mechanism underlying the efficacy of a more potent PDE4i, CC-11050, as adjunct to INH treatment in a mouse model of pulmonary Mtb infection. Genome-wide lung transcriptome analysis confirmed the dampening of inflammation and associated network genes that we previously reported with CC-3052. Consistent with the reduction in inflammation, a significant improvement in Mtb control and pathology was observed in the lungs of mice treated with CC-11050 plus INH, compared to INH alone. This important confirmatory study will be used to help design upcoming human clinical trials with CC-11050 as an HDT for TB treatment