Changes In Other Safety Parameters Research Articles

A Randomized, Double-Blind, Placebo-Controlled, 16-Week Study of the H<sub>3</sub> Receptor Antagonist, GSK239512 as a Monotherapy in Subjects with Mild-to-Moderate Alzheimer’s Disease

Histaminergic H3 receptors may play a role in modulating cholinergic and monoaminergic neurotransmission. This Phase II study evaluated the efficacy and safety of GSK239512, a highly potent, brain penetrant H3 receptor antagonist as monotherapy treatment for subjects with mild-to-moderate probable Alzheimer's disease (AD). In this 16-week, double-blind, randomized, parallel group study, 196 currently untreated subjects with mild-tomoderate AD (Mini Mental State Examination [MMSE] 16-24) received GSK239512 (n=97); or placebo (n=99) administered orally each morning. After a two-week placebo run-in period GSK239512 was up-titrated over 4 weeks in a flexible manner (10-20-40-80 microgram [µg]) followed by a 12-week Maintenance Phase. Co-primary efficacy endpoints were change from baseline in Episodic Memory and Executive Function/Working Memory composite scores from the CogState neuropsychological test battery (NTB) at Week 16. Compared to placebo, GSK239512 improved Episodic Memory at Week 16 (Effect Size [ES] =0.35; p=0.0495). No statistically significant differences were observed on other cognitive domains or on clinical measures including the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADASCog). GSK239512 treatment was associated with mild to moderate adverse events with headache, dizziness and events related to sleep disturbances being the most common and more pronounced in the early titration period when subjects were first being exposed to GSK239512 at the lower 10µg and 20µg doses. There were no clinically relevant changes in other safety parameters. GSK239512, at doses up to 80µg/day, improved Episodic Memory in patients with mildto- moderate AD. However, no improvements were observed on Executive Function/Working Memory or other domains of cognition. No changes were observed on any of the clinical measures included as secondary endpoints (including ADAS-Cog) indicating that GSK239512 failed to show benefit in this population. GSK239512 had an acceptable safety and tolerability profile. These findings suggest that H3 antagonists may, at most, have modest and selective effects on cognitive function in patients with mild-to-moderate AD.

A prospective study comparing the efficacy and safety of two sublingual birch allergen preparations.

BackgroundSUBLIVAC FIX Birch (SUB-B) is a liquid oral preparation of Betula verrucosa pollen extract for the treatment of allergic rhinitis/rhinoconjuctivitis induced by birch pollen. The major allergen content of SUB-B and Staloral Birch (Stal-B) have been shown to be comparable. In order to compare the clinical efficacy and safety of both products, the present study was designed to investigate efficacy of treatment with SUB-B compared to Stal-B by means of reduction in allergy symptoms assessed by a titrated nasal provocation test (TNPT) in subjects suffering from IgE mediated allergy complaints triggered by birch pollen.MethodsA prospective, randomized, open, blinded endpoint (PROBE), controlled, single-centre study in 74 birch allergic adults was performed. Treatment consisted of either SUB-B (10,000 AUN/ml) or Stal-B (initial phase 10 I.R./ml and maintenance phase 300 I.R./ml) for 16–20 weeks at maintenance dose. The primary efficacy outcome was defined by the difference in change of the TNPT-threshold dose between the two treatment groups at baseline and after completion of treatment. Secondary outcomes included determination of birch pollen specific IgE and IgG levels, safety lab and ECG. During the first 30 days of treatment, subjects were requested to fill out a diary concerning compliance with study medication, occurrence of AEs and the use of concomitant medication.ResultsAnalysis of the primary efficacy parameter showed that the percentage of subjects showing a beneficial treatment effect was similar in both treatment groups, 33.3% for SUB-B vs. 31.4% for Stal-B in the intention to treat population. Evaluation of the immunologic response, showed that treatment with SUB-B and Stal-B induced similar increases (approximately 2 times) in IgE, IgG and IgG4 specific for Bet v 1.In total, 143 related adverse events (AEs) were reported. The majority of the AEs was of mild intensity. The same pattern of AEs was observed for both products. No clinically relevant changes in other safety parameters, such as safety laboratory parameters, vital signs, physical examination and ECGs were observed.ConclusionTaken together, treatment with both products was effective by means of reduction in allergic symptoms during a TNPT. In addition, safety analysis revealed a good tolerability of both SLIT extracts.

Efficacy, Safety, and Acceptance of Beclomethasone Dipropionate Administered via a New Dry Powder Inhaler or a Standard CFC Metered-Dose Inhaler in Asthma Patients

Background/Objectives: The mechanical aerosol generator, MAGhaler^®, is a new chlorofluorocarbon-free inhalation device. The objective of this trial was to show equivalent efficacy and safety of beclomethasone dipropionate (BDP) delivered via the MAGhaler^® and the metered-dose inhaler (MDI) in patients with mild to moderate bronchial asthma. Moreover, user-friendliness and acceptance of the two devices were compared. Methods: This was a double-blind, reference-controlled, 12-week trial in 171 patients with asthma receiving BDP (1,000 µg/day) delivered via either the MAGhaler^® or the conventional MDI. Respiratory function parameters, clinical symptoms, concomitant intake of salbutamol or fenoterol, adverse events (AEs), laboratory values, and concomitant medications and diseases were recorded. The primary efficacy parameter was mean forced expiratory volume in 1 s (FEV₁), measured after 4, 8, and 12 weeks of therapy. Results: The equivalence of the two devices was confirmed (p = 0.003) on the basis of the ratios of the mean FEV₁ in weeks 4 to 12. Mean (± SD) FEV₁ (MAGhaler^®) was 2.24 ± 0.60 l (baseline), 2.61 ± 0.90 litres (week 4), and 2.62 ± 0.87 litres (weeks 4–12). Mean FEV₁ (MDI) was 2.28 ± 0.59 litres (baseline), 2.53 ± 0.82 litres (week 4), and 2.56 ± 0.77 litres (weeks 4–12). In total, 33 AEs occurred in 26 (30.2%) patients (MAGhaler^®) and 51 AEs in 36 (42.4%) patients (MDI). Most of the AEs were of mild or moderate intensity. The relationship to treatment could not be excluded for 11 AEs in 11 patients (MAGhaler^®) and 23 AEs in 18 patients (MDI). Three serious AEs, all unrelated to treatment, occurred in 3 patients (MAGhaler^®: 2, MDI: 1). There were no clinically relevant changes in other safety parameters. Most patients either preferred the MAGhaler^® or rated the two devices as equally acceptable. Conclusion: The new MAGhaler^® was equivalent to the standard MDI in terms of the safety and efficacy of BDP. The improved user-friendliness and acceptance of the MAGhaler^® over the conventional MDI represent an important advance in the clinical management of bronchial asthma.