A randomized, placebo-controlled trial of canakinumab in patients with peripheral artery disease.

Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1ß (IL-1ß) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1ß signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean age 65 years; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. The mean vessel wall area (by 3.0 T black-blood magnetic resonance imaging (MRI)) of the superficial femoral artery (SFA) was used to measure plaque volume. Mobility was assessed using the 6-minute walk test. Canakinumab was safe and well tolerated. Markers of systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein) fell as early as 1 month after treatment. MRI (32 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA in either placebo-treated or canakinumab-treated patients. Although an exploratory endpoint, placebo-adjusted maximum and pain-free walking distance (58 m) improved as early as 3 months after treatment with canakinumab when compared with placebo. Although canakinumab did not alter plaque progression in the SFA, there is an early signal that it may improve maximum and pain-free walking distance in patients with symptomatic PAD. Larger studies aimed at this endpoint will be required to definitively demonstrate this. ClinicalTrials.gov Identifier: NCT01731990.

An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension.

BACKGROUND: Hereditary angioedema (HAE) is characterized by recurrent attacks of subcutaneous or submucosal edema. Attacks are unpredictable, debilitating, and have a significant impact on quality of life. Patients may be prescribed prophylactic therapy to prevent angioedema attacks. Current prophylactic treatments may be difficult to administer (i.e., intravenously), require frequent administrations or are not well tolerated, and breakthrough attacks may still occur frequently. Lanadelumab is a subcutaneously-administered monoclonal antibody inhibitor of plasma kallikrein in clinical development for prophylaxis of hereditary angioedema attacks. A Phase 1b study supported its efficacy in preventing attacks. A Phase 3, randomized, double-blind, placebo-controlled, parallel-arm study has been completed and an open-label extension is currently ongoing. METHODS/DESIGN: The primary objective of the open-label extension is to evaluate the long-term safety of repeated subcutaneous administrations of lanadelumab in patients with type I/II HAE. Secondary objectives include evaluation of efficacy and time to first angioedema attack to determine outer bounds of the dosing interval. The study will also evaluate immunogenicity, pharmacokinetics/pharmacodynamics, quality of life, characteristics of breakthrough attacks, ease of self-administration, and safety/efficacy in patients who switch to lanadelumab from another prophylactic therapy. The open-label extension will enroll patients who completed the double-blind study ("rollover patients") and those who did not participate in the double-blind study ("non-rollover patients"), which includes patients who may or may not be currently using another prophylactic therapy. Rollover patients will receive a single 300 mg dose of lanadelumab on Day 0 and the second dose after the patient's first confirmed angioedema attack. Thereafter, lanadelumab will be administered every 2 weeks. Non-rollover patients will receive 300 mg lanadelumab every 2 weeks regardless of the first attack. All patients will receive their last dose on Day 350 (maximum of 26 doses), and will then undergo a 4-week follow-up. DISCUSSION: Prevention of attacks can reduce the burden of illness associated with HAE. Prophylactic therapy requires extended, repeated dosing and the results of this study will provide important data on the long-term safety and efficacy of lanadelumab, a monoclonal antibody inhibitor of plasma kallikrein for subcutaneous administration for the treatment of HAE. Trial registration NCT02741596.

Clinico-radiological correlates of achalasia.

OBJECTIVE: To study the clinical and radiographic characteristics of achalasia in a cohort Jordanian patients and to investigate the presence of any clinico-radiological relationships. METHODS: Thirty-five cases of recently diagnosed untreated achalasia patients were studied at Jordan University Hospital, Amman, Jordan during the period of January 1999 to December 2002. Measurements of maximum esophageal and gastroesophageal (GE) junction diameters, as radiographic features, were obtained from films. The clinical features included age; gender; nature; frequency and duration of typical and atypical symptoms; total number of symptoms; calculated typical symptoms score; and diagnostic delay. Pearson correlation coefficients were calculated between radiographic and clinical features, and among the radiographic features themselves. Using Spearman's correlation coefficients, the later analysis was repeated for patients with diagnostic delay of 2 years or less and patients with more than 2 years. All results were evaluated based on the 0.05 level of significance. RESULTS: There were 35 consecutive achalasia patients enrolled in this study (20 females and 15 males) with a mean age of 42.3 +/- 15.6 years and diagnostic delay of 29 +/- 26 months. On average, each patient has presented 2 typical symptoms and 2 atypical symptoms. The mean typical symptoms score was almost 3 out of the full score of 6. The mean GE junction diameter was 2.4 mms and maximum esophageal diameter was 29 mms. Maximum esophageal diameter was significantly correlated with the number of typical, atypical and total symptoms as well as with the typical symptom score and diagnostic delay. Negative correlation was found between GE junction diameter and maximum esophageal diameter; but only statistically significant for patients with diagnostic delay of more than 2 years. CONCLUSION: Statistically significant relationship exists between maximum esophageal diameter and all clinical variables. Negative correlation exists between maximum esophageal diameter and GE junction diameter; however, only significant for patients with a diagnostic delay more than 2 years. The possibility of achalasia is high in patients with longer diagnostic delay who demonstrate negative relationship between maximum esophageal diameter and GE junction diameter.

Comparison of gastric emptying parameters between asymptomatic volunteers and patients with functional dyspepsia in Middle Eastern population.

OBJECTIVE: To derive the normal reference values for Middle East population using a standard method, and to validate its performance in functional dyspepsia. METHODS: A prospective study was designed to derive gastric emptying parameters in 36 healthy control subjects. We measured the lag phase, half time, and gastric retention at the first, second, and third hours. Values were compared to 49 patients with functional dyspepsia. This study was carried out between July 2005 and August 2009 at Jordan University Hospital, Amman, Jordan. RESULTS: There were no statistically significant differences between the 2 groups at lag phase. Dyspeptic patients had significantly higher gastric retention at the first, second, and third hours (p=0.045, p=0.003, p=0.002). Gastric retention at the third hour was the most sensitive parameter detecting 16 patients (32.6%). Only 3 patients (6.1%) had increased gastric retention at the first hour and normal retention at the third hour. Twelve patients (24.5%) had delayed half time; these patients had increased gastric retention either at the first or third hour. CONCLUSION: Measurement of gastric retention at the first, second, and third hour is enough to identify delayed-early and late phases of gastric emptying in functional dyspepsia patients.