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 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.

Impact of Hippotherapy on Gross Motor Function and Quality of Life in Children with Bilateral Cerebral Palsy: A Randomized Open-Label Crossover Study

2018 ◽  
Vol 49 (03) ◽  
pp. 185-192 ◽  
Author(s):  
Ute Deutz ◽  
Nicole Heussen ◽  
Katharina Weigt-Usinger ◽  
Steffen Leiz ◽  
Christa Raabe ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Cerebral Palsy ◽  
Motor Function ◽  
Spastic Cerebral Palsy ◽  
Psychosocial Burden ◽  
Open Label ◽  
Gross Motor ◽  
Gross Motor Function ◽  
Group Data

AbstractThis study investigated the effect of hippotherapy on gross motor function (Gross Motor Function Measure [GMFM]-66, GMFM dimension E and D) and quality of life (Child Health Questionnaire [CHQ 28], KIDSCREEN-27 parental versions) in children with bilateral spastic cerebral palsy. Seventy-three children (age: 9.1 ± 3.3 years; male = 44; GMFCS levels II = 27; III = 17; IV = 29) were randomized to an early (n = 35) or late (n = 38) treatment group. Data from 66 probands were available for further analysis. Probands received hippotherapy once to twice weekly during a period of 16 to 20 weeks (mean: 17 treatments) in a crossover approach. Whereas no significant changes were found for total GMFM scores and quality of life parameters, a significant increase in GMFM dimension E was found. Children terminating the study early showed lower mean psychosocial quality of life scores than children who completed the whole study (CHQ-28 “psychosocial dimension”; KIDSCREEN-27 “mood and emotional dimension”). Our data are in line with previous reports and suggest that hippotherapy shows distinct therapeutic strengths with regard to promoting upright stand and gait in children with cerebral palsy. Children with higher psychosocial burden of disease may need special support to get access to and benefit from intensified physiotherapy programs.

Efficacy of proprietary Lactobacillus casei for anti-tuberculosis associated gastrointestinal adverse reactions in adult patients: a randomized, open-label, dose–response trial

2020 ◽  
Vol 11 (1) ◽  
pp. 370-377 ◽  
Author(s):  
Song Lin ◽  
Shanliang Zhao ◽  
Jiahong Liu ◽  
Jianwen Zhang ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Adverse Events ◽  
Treatment Failure ◽  
Lactobacillus Casei ◽  
Adverse Reactions ◽  
Open Label ◽  
Label Dose ◽  
Gastrointestinal Adverse Events ◽  
Response Trial

Anti-tuberculosis (TB) drugs can induce a series of gastrointestinal adverse events, which can seriously affect patients’ quality of life and may lead to treatment failure.

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 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 and Improved Efficacy Outcomes in Children With AADC Deficiency Treated With Eladocagene Exuparvovec Gene Therapy: Results From Three Clinical Trials

2021 ◽  
Author(s):  
Paul Wuh- Liang Hwu ◽  
Yin- Hsiu Chien ◽  
Ni- Chung Lee ◽  
Sheng- Hong Tseng ◽  
Chun- Hwei Ta ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Body Weight ◽  
Genetic Disorder ◽  
Acid Decarboxylase ◽  
Open Label ◽  
Amino Acid Decarboxylase ◽  
Safety Population ◽  
Oculogyric Crisis ◽  
Full Head ◽  
Intent To Treat

Introduction: aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder of neurotransmitter synthesis, is characterized by motor developmental deficits and clinical features associated with the autonomic nervous system, including dyskinesia, and oculogyric crisis. Objective: To evaluate clinical outcomes in children with AADC deficiency treated with eladocagene exuparvovec, a recombinant adeno-associated virus vector containing the human cDNA encoding the AADC enzyme. Methods: In 3 open-label clinical studies, children with AADC deficiency who had no full head control and no ability to sit, stand, or walk received eladocagene exuparvovec as bilateral, intraputaminal, stereotactic infusions during a single operative session (total dose, 1.8 x 1011vg). Body weight, oculogyric crisis episodes, and adverse events (AE) were recorded. Results: In the 3 studies, patients aged 21 months to 8.5 years (N=26) received eladocagene exuparvovec, constituting the safety population. In the intent-to- treat population (N=21), mean body weight at baseline was 12.0 kg (median 10.5 kg) and increased to 15.2 kg (median 13.2 kg) at 12 months posttreatment. Frequency of oculogyric crises was improved at 12 months posttreatment. Dyskinesia was recorded as an AE in 23 patients in the safety population; most events were mild or moderate, occurred within 3 months after eladocagene exuparvovec treatment, generally responded to standard pharmacotherapy, and resolved in all patients by 10 months. Conclusions: In children with AADC deficiency who received eladocagene exuparvovec gene therapy, body weight increased and oculogyric crises and dyskinesia improved.

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