AbobotulinumtoxinA provides flexibility for the treatment of cervical dystonia with 500 U/1 mL and 500 U/2 mL dilutions.

INTRODUCTION: Cervical dystonia (CD) is a neurologic movement disorder with potentially disabling effects and significant impact on quality of life of those affected. AbobotulinumtoxinA (aboBoNT-A) was initially approved for a dilution of 500 U/1 mL and subsequently for a dilution of 500 U/2 mL, providing flexibility for clinicians to treat CD. Here, we explore the safety and efficacy of the 500 U/2 mL dilution versus 500 U/1 mL dilution of aboBoNT-A in a retrospective analysis based on published clinical trial data. METHODS: The safety and efficacy of aboBoNT-A in patients with CD was evaluated in three multicenter, double-blind, randomized, placebo-controlled trials and open-label extensions. Trials 1 (NCT00257660) and 2 (NCT00288509) evaluated the 500 U/1 mL dilution in 80 and 116 patients, respectively; Trial 3 (NCT01753310) evaluated the 500 U/2 mL dilution in 125 patients. RESULTS: Comparison of the adjusted mean difference in TWSTRS total scores at Week 4 from baseline for aboBoNT-A in Trial 1 (-6.0; 95% CI, -10.8, -1.3), Trial 2 (-8.8; 95% CI, -12.9, -4.7), and Trial 3 (-8.7; 95% CI, -13.2, -4.2) showed similar, significant improvements. Dysphagia and muscle weakness patterns were comparable across the three trials, indicating that an increased dilution of aboBoNT-A does not result in an increased risk of diffusion-related adverse events. CONCLUSION: The results of these trials show that aboBoNT-A is similarly efficacious using either dilution, with similar safety and tolerability across trials. Having the 500 U/1 mL and 500 U/2 mL dilution volumes available provides further flexibility in administration, benefiting patient care.

Correction: Sustained functional benefits after a single set of injections with abobotulinumtoxinA using a 2-mL injection volume in adults with cervical dystonia: 12-week results from a randomized, double-blind, placebo-controlled phase 3b study.

[This corrects the article DOI: 10.1371/journal.pone.0245827.].

Sustained functional benefits after a single set of injections with abobotulinumtoxinA using a 2-mL injection volume in adults with cervical dystonia: 12-week results from a randomized, double-blind, placebo-controlled phase 3b study.

Cervical dystonia (CD) is primarily treated with botulinum toxin, at intervals of ≥ 12 weeks. We present efficacy, patient-reported outcomes (PROs), and safety in adults with CD at the last available visit after a single set of abobotulinumtoxinA (aboBoNT-A) injections versus placebo using 500 U in a 2-mL injection volume. In this 12-week, randomized, double-blind trial, patients were ≥ 18 years of age with primary idiopathic CD, had a Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥ 20, and TWSTRS-Severity subscale score > 10 at baseline. Patients (N = 134) were randomized (2:1) to aboBoNT-A (n = 89) or placebo (n = 45), with aboBoNT-A patients treated with 500 units (U) if toxin-naïve, and 250 to 500 U based on previous onabotulinumtoxinA dose if non-naïve. Endpoints included total TWSTRS, Pain Numeric Rating Scale (NRS-Pain; 24-hour), Treatment Satisfaction Questionnaire for Medication, and other PROs for pain, depression, and global health. Results are for the intent-to-treat population, with "Week 12" (Wk12) comprising the last available post-baseline assessment (end-of-study or early withdrawal). Mean TWSTRS total scores improved from 42.5 at baseline to 35.4 at Wk12 with aboBoNT-A and 42.4 to 40.4 with placebo (treatment difference: -4.8; 95% confidence interval [CI]: -8.5, -1.1; p = 0.011). At Wk12, mean (95% CI) change from baseline in NRS-Pain was -1.0 (-1.59, -0.45) for aboBoNT-A and -0.2 (-0.96, 0.65) for placebo. AboBoNT-A demonstrated numeric improvements in other PROs. More aboBoNT-A-treated patients than patients receiving placebo reported being at least "somewhat satisfied" with treatment (60.4% vs 42.2%, respectively), symptom relief (57.0% vs 40.0%), and time for treatment to work (55.8% vs 33.3%). No new adverse events were reported. Results indicate that in patients with CD, treatment with aboBoNT-A using a 2-mL injection provided sustained improvement in the TWSTRS total score and patient-perceived benefits up to 12 weeks. Trial registration: Clinicaltrials.gov Identified: NCT01753310.

AbobotulinumtoxinA using 2-mL dilution (500 U/2-mL) maintains durable improvement across multiple treatment cycles.

BACKGROUND: Cervical dystonia (CD), the most common focal dystonia, is a chronic neurological movement disorder characterized by sustained involuntary contractions of the neck muscles, leading to abnormal postures. AbobotulinumtoxinA (aboBoNT-A) was approved in the US initially as a 500 U per 1-mL dilution and subsequently, as a 500 U/2-mL dilution (or 250 U/mL), thereby providing clinicians with more flexible dosing options to better meet individual patient needs. The objective of this open-label extension study was to evaluate the longer term safety and efficacy of repeat treatments with aboBoNT-A using 2-mL dilutions in adults with cervical dystonia. METHODS: Patients (N = 112) from a 12-week, double-blind lead-in study (NCT01753310) received up to three additional treatments of aboBoNT-A, with re-treatment every 12-16 weeks based on clinical judgment. Safety was assessed through treatment-emergent adverse events (TEAEs). The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total and subscale scores were measured at day 1 of each treatment cycle (C), 4 weeks after each treatment, and 12 weeks after the third treatment. Descriptive statistics were used for all analyses. RESULTS: In cycles 1, 2, 3, and 4, respectively, 35.7, 25.9, 30.2, and 22.8% of patients reported TEAEs. Dysphagia, muscular weakness, and neck pain were each reported by 10.7% of patients, over the full study duration. Mean TWSTRS total score decreased from 37.7 (SD 13.6 [C1, day 1]) to 30.1 (SD 12.8 [C3, week 12]). In each cycle, TWSTRS total and subscale scores decreased from day 1 to week 4 and increased between weeks 4 and 12, though the week 12 scores remained lower than day 1 scores. CONCLUSION: Extended treatment of cervical dystonia with aboBoNT-A (up to 3 additional treatment cycles) using a 2-mL dilution is effective, with a positive risk-benefit profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01753336. Registered 17 Dec 2012.

Octagam® for chronic inflammatory demyelinating polyneuropathy: results from three observational studies.

AIM: To present data from three studies of a Post-Authorization Safety Surveillance (PASS) program for the subset of patients receiving Octagam® 5% or 10% for chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Data on patients with CIDP treated with Octagam were analyzed to assess its safety and tolerability. RESULTS: Of 2314 patients included in the studies, 58 patients (mean age: 64.6 years) received Octagam for CIDP, mean dose of which was 0.8 g/kg bodyweight/course. 81% of observations for clinical appearance since last observation were assessed as stable and 16.6% showed an improved clinical appearance with treatment. Adverse drug reactions were rare (<0.7% of infusions). CONCLUSION: Octagam was effective and well-tolerated in patients with CIDP.

Tolerability and safety of the intravenous immunoglobulin octagam® 10% in patients with immune thrombocytopenia: a post-authorisation safety analysis of two non-interventional phase IV trials.

OBJECTIVES: To provide detailed data on the tolerability and safety of octagam® 10%, a ready-to-use intravenous immunoglobulin, in a subgroup of patients with immune thrombocytopenia (ITP) involved in an integrated analysis of post-authorisation safety surveillance (PASS) studies. METHODS: A subgroup analysis was conducted using data collected from two non-interventional studies that included patients with ITP treated with octagam® 10%. Patients were observed and monitored for possible adverse drug reactions (ADRs) during or after administration of octagam® 10%, with a particular focus on thromboembolic events (TEEs). ADRs were analysed at the case and event level. RESULTS: In this analysis of 112 patients receiving octagam® 10% (mean dose 0.4 g/kg/infusion), there were five cases with at least one adverse drug reaction (ADR) associated with 626 infusions of octagam® 10% (case incidence of 0.8% per infusion). ADRs were of mild or moderate severity. There were a total of 10 events, most commonly back pain (n = 3) and headache (n = 2). Nausea, dizziness and a sensation of heaviness were also reported. The remaining two events involved drug exposure during pregnancy. There were no TEEs or other serious ADRs. DISCUSSION: In this subgroup analysis of patients who received octagam® 10% (manufactured using an amended process) in two PASS studies, the overall ADR rate was low, with ADRs occurring in only 0.8% of all infusions. No TEEs or other serious ADRs were reported. CONCLUSIONS: Routine clinical use of octagam® 10% was safe and well tolerated, with no unexpected safety issues, in patients with ITP. The two studies from which data were taken are registered with the International Standard Randomised Controlled Trial Number Registry, numbers ISRCTN58800347 and ISRCTN02245668.

Tolerability and safety of Octagam® (IVIG): a post-authorization safety analysis of four non-interventional phase IV trials
.

OBJECTIVE: To evaluate the tolerability and safety of Octagam® 5% and 10% across all indications, ages, and treatment regimens, using data from four non-interventional post-authorization safety studies (PASS); this analysis was performed following changes in the preparation of raw material used to manufacture Octagam. METHODS: All four studies included in- and out-patients prescribed Octagam for treatment of their medical condition. Physicians used case report forms to document baseline demographics, Octagam treatment details, and data on the efficacy of Octagam, and recorded all adverse drug reactions (ADRs) and other safety data. RESULTS: Altogether 21,780 infusions of Octagam in 2,397 patients were included in our analysis. The most frequent indication for Octagam was secondary immunodeficiencies (SID; n = 1,368, 11,348 infusions), followed by primary immunodeficiencies (PID; n = 363; 3,923 infusions). During the individual patient observation, 83% of SID and 67% of PID patients were free of any infection. In up to 85% of all investigator assessments, Octagam was rated to have a favorable effect. In autoimmune diseases, investigators assessed Octagam as being beneficial in 70% (immune thrombocytopenia) up to 100% (Guillain-Barré syndrome), depending on the indication. The majority of patients (92%) tolerated Octagam treatment without any ADR. The overall incidence of reported ADRs was 1.0% for all infusions. The majority of ADRs were considered non-serious (93%) and mild or moderate (87%) in severity. No unexpected ADR signal was detected. CONCLUSIONS: This analysis demonstrates that the changes in the preparation of raw material used to manufacture Octagam did not affect the safety profile of Octagam® 5% and 10%.
 *At the time of study realization.

Predicting therapeutic efficacy of intravenous immunoglobulin (IVIG) in individual patients with relapsing remitting multiple sclerosis (RRMS) by functional genomics.

PURPOSE: Only a fraction of patients do benefit from disease modifying treatments in RRMS and data on IVIG are controversial, it has been suggested that there is a subpopulation of patients with good clinical response to IVIG. METHODS: In the prospective, multicenter, open label, exploratory study RRMS patients receiving IVIG therapy were genotyped and several immune parameters were collected. RESULTS: To distinguish between potential responders and non-responders each of the observed genotypes was combined with the corresponding scores of 65 immune parameters in a stepwise approach. Non-responders were defined as being positive for 4 or more out of 9 individual scores. Responders scored either 0 or 1, while non-responders scored between 7 and 9 (p=1.2∗10(-7)). CONCLUSIONS: In summary, combination of genomic and functional immune parameters allowed prospective discrimination between responders and non-responders towards IVIG therapy in this learning panel of RRMS patients and will be confirmed in a validation study.

Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid ß (Aß)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aß(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aß(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.

Non-antisense cellular responses to oligonucleotides.

Oligonucleotides induce various cellular responses which are not due to the blockade of protein synthesis by an antisense mechanism. Oligonucleotides presenting double-stranded or G-quartet structures (ribo- or deoxyribonucleotides, phosphodiester or phosphorothioated) induce retraction of neurites and aggregation of chicken retinal cells within 10-20 h. This effect is reversible, non-toxic; it appears to require internalization and can be mimicked by treatment of the cells with an RGDS peptide. The oligonucleotides appear to trigger a cascade of intracellular events, affecting the adhesive properties of integrins. In addition, a subset of oligonucleotides induced platelet aggregation, probably through their interaction with membrane receptors. Recognition of these effects is important for the design and interpretation of antisense experiments.