scholarly journals N-acetyl-L-leucine improves symptoms and functioning in GM2 Gangliosidosis (Tay-Sachs & Sandhoff)

2021 ◽  
Author(s):  
Kyriakos Martakis ◽  
Jens Claassen ◽  
Jordi Gascon-Bayarri ◽  
Nicolina Goldschagg ◽  
Andreas Hahn ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Rating Scales ◽  
Therapeutic Option ◽  
Baseline Period ◽  
Clinical Impression ◽  
Gm2 Gangliosidosis ◽  
Open Label ◽  
Serious Adverse Events ◽  
Intention To Treat

Background and Objective: GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are rare, inherited neurodegenerative disorders with no available symptomatic or disease modifying treatments. This clinical trial aimed to investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms of pediatric (greater than or equal to 6 years) and adult patients with GM2 gangliosidosis. Methods: We conducted an 8-center, multi-national, open-label, rater-blinded Phase IIb study (IB1001-201). Patients with a genetically confirmed diagnosis of GM2 gangliosidosis were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients greater than or equal to 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9Hole Peg Test) during each study periods. Secondary outcomes included cerebellar rating scales (namely Scale for the Assessment and Rating of Ataxia), clinical global impression, and quality of life assessments. Results: 30 patients aged 6 to 55 years with a confirmed diagnosis of GM2 gangliosidosis (TaySachs or Sandhoff's disease) were enrolled. 29 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.71, SD=2.09, 90% CI 0.00, 1.50, p=0.044), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions: This study showed NALL led to a statistically significant improvement in symptoms, functioning, and quality of life in patients with GM2 gangliosidosis. It is a safe, well-tolerated, easily administered oral therapy, therefore offering a favorable risk/benefit profile for this serious, debilitating disorder. NALL is a new therapeutic option for the treatment of this rare disease that has no other approved therapies worldwide. Classification of Evidence: This study provides Class IV evidence NALL is safe, well-tolerated, and improves neurological symptoms and quality of life in patients with GM2 gangliosidosis. Trial Registration Information: The trial is registered with ClinicalTrials.gov (NCT03759665; registered 30-Nov-2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled 07-June-2019.

scholarly journals Safety of Denervation Following Targeted Lung Denervation Therapy for COPD: AIRFLOW-1 Three-year Outcomes

2020 ◽  
Author(s):  
Christophe Pison ◽  
Pallav Shah ◽  
Dirk-Jan Slebos ◽  
Vincent Ninane ◽  
Wim Janssens ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Lung Function ◽  
Adverse Events ◽  
Late Onset ◽  
Open Label ◽  
Serious Adverse Events ◽  
Copd Exacerbations ◽  
Clinical Consequences

Abstract Background: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over three years of follow up.Methods: TLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at one, two, and three years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life. Results: Three-year follow-up data were available for 73.9% of patients (n=34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV1, FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over three years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed. Conclusion: TLD in COPD patients demonstrated a positive safety profile out to three years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over three years of follow up.

scholarly journals Safety of denervation following targeted lung denervation therapy for COPD: AIRFLOW-1 3-year outcomes

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Pison Christophe ◽  
L. Shah Pallav ◽  
Slebos Dirk-Jan ◽  
Ninane Vincent ◽  
Janssens Wim ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Lung Function ◽  
Adverse Events ◽  
Late Onset ◽  
Open Label ◽  
Serious Adverse Events ◽  
Copd Exacerbations ◽  
Clinical Consequences

Abstract Background Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow up. Methods TLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at 1, 2, and 3 years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life. Results Three-year follow-up data were available for 73.9% of patients (n = 34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV1, FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over 3 years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed. Conclusion TLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over 3 years of follow up.

scholarly journals Open-label placebos for menopausal hot flushes: a randomized controlled trial

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yiqi Pan ◽  
Ramona Meister ◽  
Bernd Löwe ◽  
Ted J. Kaptchuk ◽  
Kai J. Buhling ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Controlled Trial ◽  
Hot Flushes ◽  
Open Label ◽  
Safe Alternative ◽  
Intention To Treat ◽  
Treatment Benefits ◽  
Hot Flush ◽  
Related Quality

AbstractThis study investigated the efficacy of an open-label placebo (OLP) treatment for menopausal hot flushes. Women with at least five moderate or severe hot flushes per day were allocated to receive four weeks of OLP for twice a day or no-treatment. Intention-to-treat analyses included n = 100 women. In comparison to no-treatment, OLP reduced the log-transformed hot flush composite score (frequency × intensity) (mean difference in change: − 0.32, 95% CI [− 0.43; − 0.21], p < 0.001, Cohen’s d = 0.86), hot flush frequency (− 1.12 [− 1.81; − 0.43], p = 0.02, Cohen’s d = 0.51), and improved overall menopause-related quality of life (− 2.53 [− 4.17; − 0.89], p = 0.02, Cohen’s d = 0.49). Twelve (24%) (vs. three [6%]) patients had 50% lesser hot flushes. Problem rating of hot flushes and subdomains of quality of life did not improve. After four weeks, the OLP group was further divided via randomization to continue or discontinue the treatment. Benefits were maintained at week 8 (log-transformed score: − 0.04 [− 0.06; 0.14], p = 0.45). There was no difference between taking placebos for 8 or 4 weeks (log-transformed score: 0.04 [− 0.17; 0.25], p = 0.73). Results indicate that open-label placebos may be an effective, safe alternative for menopausal hot flushes.

scholarly journals Efficacy and safety of N-acetyl-l-leucine in Niemann–Pick disease type C

2021 ◽  
Author(s):  
Tatiana Bremova-Ertl ◽  
Jens Claassen ◽  
Tomas Foltan ◽  
Jordi Gascon-Bayarri ◽  
Paul Gissen ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Washout Period ◽  
Rating Scales ◽  
Disease Type ◽  
Clinical Impression ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

Abstract Objective To investigate the safety and efficacy of N-acetyl-l-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann–Pick disease type C (NPC) patients. Methods In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6–12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. Results 33 subjects aged 7–64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. Clinicaltrials.gov identifier NCT03759639.

scholarly journals Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012952
Author(s):  
Chadwick W. Christine ◽  
R. Mark Richardson ◽  
Amber D. Van Laar ◽  
Marin E. Thompson ◽  
Elisabeth M. Fine ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Gene Therapy ◽  
Motor Function ◽  
Motor Fluctuations ◽  
Acid Decarboxylase ◽  
Open Label ◽  
Serious Adverse Events ◽  
Amino Acid Decarboxylase ◽  
Label Dose

Objective:To report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson’s disease (PD) and motor fluctuations.Methods:PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic L-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5x1011 vector genomes (vg); cohort 2, ≤1.5x1012 vg; cohort 3, ≤4.7x1012 vg.Results:No serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector–related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, UPDRS III off-medication and on-medication scores), global impressions of improvement (CGI-I, PGI-I), and quality of life (PDQ-39) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts.Conclusions:VY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years.Clinicaltrials.gov identifier: NCT01973543Classification of evidence:This study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

scholarly journals AYUSH medicine as add-on therapy for mild category COVID-19; an open label randomised, controlled clinical trial

2020 ◽  
Author(s):  
Anusha Rao ◽  
R Ranganatha ◽  
G Vikneswaran ◽  
C Sagar ◽  
R Mathu ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Standard Care ◽  
Controlled Trial ◽  
Intervention Group ◽  
Controlled Clinical Trial ◽  
P Value ◽  
Open Label ◽  
Serious Adverse Events ◽  
Negative Conversion

AbstractBackgroundAYUSH formulations have a potential role in symptomatic treatment, preventing disease progression and improving quality of life in COVID-19 patients.ObjectiveTo study the effect of AYUSH formulation (Kabasura Kudineer tablets, Shakti drops and Turmeric plus) as an add-on treatment in patients with mild COVID - 19MethodologySingle centre, two arms, open labelled randomized controlled trial with a total of 30 patients (15 in the intervention arm and 15 in the standard care arm). Intervention arm received a combination of 3 AYUSH formulation along with the standard of care treatment for 21 days. All patients were followed for 28 days. Symptom severity (using Modified Jackson scale), negative conversion of SARS-CoV-2 RNA (using RTPCR) and quality of life (WHOWOL BREF questionnaire) was assessed.ResultsFifteen patients (93.8%) in the intervention group and twelve patients (92.3%) in the standard care arm had complete resolution of symptoms (P value= 0.36). Negative conversion for SARS-CoV-2 was seen in thirteen patients (92.9%) in intervention arm and eleven patients (100%) in standard care arm at day 28 (P value = 0.56). There was no difference in the quality of life scores between the 2 groups.ConclusionThe use of Ayush interventions as add-on therapy did not negatively impact the clinical outcomes in COVID-19. This trial confirmed the safety and tolerability of Kabasura Kudineer tablets, Shakti drops and Turmeric plus tablets when used use among mild to moderate symptom category, of COVID-19. There were no serious adverse events in the treated group. There was no clinical progression of disease from baseline status and all trial participants recovered fully by day 28. A longer follow up and a larger sample size is recommended for future definitive trials with this alternative medicine (AYUSH) combination.

Cathartic Effect of Suicide Attempts Not Limited to Depression

Crisis ◽  
2003 ◽  
Vol 24 (2) ◽  
pp. 73-78 ◽  
Author(s):  
Yves Sarfati ◽  
Blandine Bouchaud ◽  
Marie-Christine Hardy-Baylé
Keyword(s):  
Quality Of Life ◽  
Depressive Symptoms ◽  
Personality Traits ◽  
Rating Scales ◽  
Suicide Attempts ◽  
World Health ◽  
Life Questionnaire ◽  
Short Term

Summary: The cathartic effect of suicide is traditionally defined as the existence of a rapid, significant, and spontaneous decrease in the depressive symptoms of suicide attempters after the act. This study was designed to investigate short-term variations, following a suicide attempt by self-poisoning, of a number of other variables identified as suicidal risk factors: hopelessness, impulsivity, personality traits, and quality of life. Patients hospitalized less than 24 hours after a deliberate (moderate) overdose were presented with the Montgomery-Asberg Depression and Impulsivity Rating Scales, Hopelessness scale, MMPI and World Health Organization's Quality of Life questionnaire (abbreviated versions). They were also asked to complete the same scales and questionnaires 8 days after discharge. The study involved 39 patients, the average interval between initial and follow-up assessment being 13.5 days. All the scores improved significantly, with the exception of quality of life and three out of the eight personality traits. This finding emphasizes the fact that improvement is not limited to depressive symptoms and enables us to identify the relative importance of each studied variable as a risk factor for attempted suicide. The limitations of the study are discussed as well as in particular the nongeneralizability of the sample and setting.

scholarly journals Duloxetine versus ‘active’ placebo, placebo or no intervention for major depressive disorder; a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Faiza Siddiqui ◽  
Marija Barbateskovic ◽  
Sophie Juul ◽  
Kiran Kumar Katakam ◽  
Klaus Munkholm ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Systematic Review ◽  
Sequential Analysis ◽  
Citation Index ◽  
Trial Sequential Analysis ◽  
Random Errors ◽  
Major Depressive ◽  
Serious Adverse Events ◽  
Meta Analyses

Abstract Background Major depression significantly impairs quality of life, increases the risk of suicide, and poses tremendous economic burden on individuals and societies. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is a widely prescribed antidepressant. The effects of duloxetine have, however, not been sufficiently assessed in earlier systematic reviews and meta-analyses. Methods/design A systematic review will be performed including randomised clinical trials comparing duloxetine with ‘active’ placebo, placebo or no intervention for adults with major depressive disorder. Bias domains will be assessed, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed. We will conduct meta-analyses. Trial sequential analysis will be conducted to control random errors, and the certainty of the evidence will be assessed using GRADE. To identify relevant trials, we will search Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, PsycINFO, Science Citation Index Expanded, Social Sciences Citation Index, Conference Proceedings Citation Index—Science and Conference Proceedings Citation Index—Social Science & Humanities. We will also search Chinese databases and Google Scholar. We will search all databases from their inception to the present. Two review authors will independently extract data and perform risk of bias assessment. Primary outcomes will be the difference in mean depression scores on Hamilton Depression Rating Scale between the intervention and control groups and serious adverse events. Secondary outcomes will be suicide, suicide-attempts, suicidal ideation, quality of life and non-serious adverse events. Discussion No former systematic review has systematically assessed the beneficial and harmful effects of duloxetine taking into account both the risks of random errors and the risks of systematic errors. Our review will help clinicians weigh the benefits of prescribing duloxetine against its adverse effects and make informed decisions. Systematic review registration PROSPERO 2016 CRD42016053931

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