Active Aβ immunotherapy CAD106 in Alzheimer's disease: A phase 2b study
Rik VandenbergheMarie‐Emmanuelle RiviereAngelika CaputoJudit SóvágóR. P. MaguireMartin R. FarlowGiovanni MarottaRaquel Sánchez‐VallePhilip ScheltensJ. Michael RyanAna Graf
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Abstract Introduction This randomized, double‐blind, placebo‐controlled, 90‐week study assessed safety, tolerability, and immunogenicity of CAD106 with/without adjuvant in patients with mild Alzheimer's disease. Methods One hundred twenty‐one patients received up to seven intramuscular injections of CAD106 (150 μg or 450 μg) or placebo ± adjuvant over 60 weeks. An amyloid positron emission tomography (PET) substudy was also conducted. Results CAD106 induced strong serological responses (amyloid‐beta [Aβ]–Immunoglobuline G[IgG]) in 55.1% (150 μg) and 81.1% (450 μg) of patients (strong serological responders [SSRs]). Serious adverse events (SAEs) were reported in 24.5% (95% confidence interval [CI] 16.7–33.8) of the patients in the active treatment group and in 6.7% (95% CI 0.2–31.9) in the placebo group. Three of the SAEs were classified as possibly related to study drug by the investigators. No evidence of central nervous system inflammation was found. Amyloid‐related imaging abnormalities (ARIAs) occurred in six cases, all of them were strong serological responders. None of the ARIAs were symptomatic. Serum Aβ‐IgG titer area under the curves correlated negatively with amyloid PET standardized uptake value ratio percentage change from baseline to week 78 within the CAD106‐treated patients (r = −0.84, P = .0004). Decrease in cortical gray‐matter volume from baseline to week 78 was larger in SSRs than in controls ( P = .0077). Discussion Repeated CAD106 administration was generally well tolerated. CAD106 450 μg with alum adjuvant demonstrated the best balance between antibody response and tolerability.Keywords:
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Fourteen cases of depression resistant to multiple treatments were treated by lithium augmentation of fluoxetine. Tolerability of the treatment was poor. Lithium and fluoxetine may be a possible treatment for resistant depression but there is caution regarding tolerability and toxicity with the relatively high doses of lithium used in this series.
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Onabotulinumtoxin A (onabotA) has shown efficacy in chronic migraine (CM), with good tolerability and a low rate of adverse effects, most of them not severe. The aim of this study is to evaluate tolerability and adverse effects of onabotA in clinical practice and to analyze if there is a relationship between tolerability to treatment administration, adverse effects' (AEs) occurrence and clinical response. We included patients with CM that received treatment with onabotA for the first time. Tolerability to treatment was evaluated by a 0-10 numeric rating scale (0: worst possible, 10: optimal tolerability). We assessed the presence of AEs by using a standardized questionnaire. Treatment response was based on the 50 and 75% responder rate between weeks 20 and 24, compared with the baseline, according to headache diaries. We analyzed whether the tolerability was associated with a higher frequency of AEs or a higher probability of clinical response. We included 105 patients, 87.7% female, with an age of 43.9 ± 10.7 years. Mean tolerability was 7.8/10 and 7.2/10 in the first and second onabotA administration, respectively. AEs were reported by (first-second) 71.4-68.6% patients. The percentage of patients with a 50% response was 56.3%. There was no association between tolerability and AEs' occurrence or clinical response.
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Inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis often present in sensitive and thin-skinned areas that are at higher risk for topical treatment-related skin irritation (e.g., burning, stinging). Our objective was to address the need for topical treatments that can be safely applied to these areas. We assessed the local tolerability of crisaborole topical ointment when applied to sensitive and thin-skinned areas of healthy volunteers. In this phase I, randomized, double-blind, vehicle-controlled, single-center study, 32 subjects were randomized 3:1 to twice-daily application of crisaborole topical ointment, 2 %, (n = 24) or vehicle ointment (n = 8) for 21 days to 13 anatomic skin areas, including the face/hairline, genitals, extensor, and intertriginous areas. The primary endpoint was assessment of the frequency and severity of local tolerability symptoms (burning/stinging, erythema, and pruritus) using the Local Tolerability Scale. Overall, 98.8 % of all tolerability assessments had a grade of 0 (no signs/symptoms of irritation) and 0.1 % had a grade >1 (mild); no differences were observed in the frequency of local tolerability scores between treatment groups. The total frequency of local tolerability assessments graded >0 (none) was lower across all application sites with crisaborole ointment (0.0–2.2 %) than with vehicle ointment (2.4–7.1 %). Local tolerability did not change over time, and was comparable between sensitive and nonsensitive skin areas. Crisaborole ointment application to sensitive skin areas was well tolerated in healthy volunteers, supporting its potential role as a topical treatment alternative for patients with AD or psoriasis.
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The paper considers the tolerability of Voltaren versus other nonsteroidal anti-inflammatory drugs, including generics. A wealth of clinical experience in using Voltaren leads to the conclusion on its good tolerability and significant anti-inflammatory and analgesic activities.
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Skin lesions, increased transepidermal water loss, changes in pH in patients with allergodermathosis lead to a decrease in the protective mechanisms of the skin that makes individuals more susceptible to infections. The development of complications predefined the interest in improving topical therapy. The article presents a brief review of the literature data on high therapeutic activity and good tolerability of the topical drug Triderm. When compared with the original drug, the generics revealed differences in the structural and mechanical properties, which affects bioavailability. A comparison of therapeutic efficacy and tolerability has shown that Triderm is more effective, and comparable to Akriderm GK in terms of tolerability.
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Objective: To assess the tolerability and safety of aildenafil citrate tablet in healthy Chinese male volunteers.Methods: Twenty-eight healthy Chinese male subjects were recruited to the single dose study.They were divided into 30,60,90 and 120 mg dose step with 30 mg as the first dose step;safety and tolerability findings at the previous dose level were the basis for the decision to proceed to the next higher dose level.Thirty-six healthy Chinese male subjects were enrolled to the multiple dose study,and the escalated dose level were 30,45 and 60 mg·d-1,once daily for continuous 3 days.The safety was assessed based on clinical symptoms and adverse events.Results: In the single dose study,the adverse events judged by the investigator to be related to aildenafil citrate tablet were abnormal vision(35.7%),flushing(21.4%),headache or dizziness(17.9%).In the multiple dose study,the adverse events related to aildenafil citrate tablet were flushing(7.4%),headache or dizziness(7.4%).There were no serious adverse events;all adverse events were mild in severity and resolved without any treatment.There were no clinically significant changes in vital signs,clinical laboratory tests and ophthalmological examination.Conclusion: Aildenafil citrate tablet is safe and well-tolerated in Chinese male healthy subjects after single doses of 30~120 mg and multiple doses of 30~60 mg,qd for 3 days.
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Summary: Purpose: To evaluate the tolerability and safety of gabapentin (GBP) as add‐on therapy for seizure control. Methods: Conducted in an outpatient setting and reflecting usual practice, this study compared tolerability of GBP dosages ≤1,800 versus >1,800 mg/day, when these doses were required to achieve the most effective seizure control. Two analyses of adverse events are presented: tolerability and safety. In the tolerability analysis, each patient served as his or her own control to compare the occurrence of adverse events at GBP ≤1,800 versus >1,800 mg/day. The safety analysis required patients to receive at least one dose of GBP and have a follow‐up contact. Results: A total of 2,216 patients enrolled in this open‐label, 16‐week study and were evaluable for safety. Of these, 74.0% completed the 16‐week study, and 281 met the tolerability criteria. Within these 281 patients, two mutually exclusive groups were compared (a) those reporting adverse events at only ≤1,800 mg/day (low dose); and (b) those reporting adverse events at only >1,800 mg/day (high dose). Three adverse events (asthenia, headache, and dizziness) were observed in a statistically significantly larger number of patients at only the low dose than in the group reporting these same adverse events at only the high dose, suggesting that patients who tolerated GBP at ≤1,800 mg/day did not experience a significant increase in adverse events with dosages >1,800 mg/day. Overall, 10.6% of the 2,216 patients in the safety population prematurely withdrew because of adverse events, and 3.5% discontinued because of lack of efficacy. Safety and tolerability of GBP was rated as excellent or good for 78.5% of all patients. Conclusions: Gabapentin doses >1,800 mg/day were as well tolerated as doses ≤1,800 mg/day and were not associated with more adverse events.
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Drug tolerability refers to the degree to which drugs' overt adverse effects can be tolerated by patients. The tolerability profile is of comparative importance to its efficacy and safety, as it largely determines adherence to treatment and ultimately treatment success or failure. However, the term is frequently used imprecisely, and it is unclear if tolerability is limited to subjective patient-reported symptoms or also covers certain objective signs and findings. The aim of this systematic review was to assess how clinical studies define, evaluate and present drug tolerability.The study consisted of a systematic review of clinical studies in PubMed® reporting the term "tolerability".Eighty clinical studies were screened and 56 studies reporting drug tolerability were retained. None of the retained studies defined events encompassed by the term tolerability by making a distinction between safety and tolerability. Twenty-five studies claimed to evaluate tolerability, but none of them described how to evaluate tolerability from the patient perspective. Most studies (54 out of 56) concluded that the treatment was well tolerated, apparently implying favourable safety. However, none of them actually presented tolerability in terms of a contrast between safety and tolerability.Tolerability is used frequently, albeit incorrectly, to refer to a drug's favourable safety profile. Focused evaluation of drug tolerability (i.e., the patient perspective of adverse drug reactions) should become routine. Presentation in regulatory documents, such as risk management plan summaries, product information and patient leaflets should be a continuation of the process of patient-centred healthcare.
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Thirty to 40% of patients using topical treatments do not comply with their treatment regimen.To examine how tolerability is assessed, tolerability ratings, and clinical significance of tolerability ratings of topical antimicrobials for acne.A literature search was performed using the terms "tolerability AND acne AND (benzoyl peroxide OR antimicrobial OR clindamycin OR erythromycin OR dapsone OR sulfur OR sulfacetamide)." Inclusion criteria were: 1) evaluation of tolerability, 2) use of an identified topical antimicrobial for acne treatment without combination retinoid use, 3) an original study, in English.Thirty-four of 132 articles met the inclusion criteria. Tolerability was measured through subject and investigator assessment of specific tolerability parameters and by reporting of adverse events. Nearly all of the acne treatments were well tolerated. Treatment related study discontinuation rates were low and had little to no relation to the degree of tolerability measures.Patients may be more adherent in clinical trials than in clinical practice. Differences in the measure used to assess tolerability make comparisons difficult.Topical antimicrobial acne therapy is generally well tolerated. Discontinuation rates are low under study conditions. Tolerability of topical antimicrobial therapy for acne may not have great clinical significance.
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Many clinical trials, including those in pediatric populations, use a placebo arm for medical conditions for which there are readily available therapeutic interventions. Several short-term efficacy trials of antihypertensive medications performed in response to Food and Drug Administration–issued written requests have used a placebo arm; whether the use of a placebo arm is safe in children with hypertension is unknown. We sought to define the rates of adverse events in 10 short-term antihypertensive trials to determine whether these trials resulted in increased risk to pediatric patients receiving placebo. We combined patient-level data from 10 antihypertensive efficacy trials performed in pediatric patients that were submitted to the Food and Drug Administration from 1998 to 2005. We determined the number and type of all of the adverse events reported during the placebo-controlled portion of the clinical trials and compared these numbers between the patients who received placebo and those who received active drug. Among the 1707 children in the 10 studies, we observed no differences in the rates of adverse events reported between the patients who received placebo and those who received active drug. Only 5 patients suffered a serious adverse event during the trials; none were thought by the investigators to be related to study drug, and only 1 occurred in a patient receiving placebo. Short-term exposure to placebo in pediatric trials of antihypertensive medications appears to be safe.
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