Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Nemonoxacin (TG-873870), a Novel Potent Broad-Spectrum Nonfluorinated Quinolone, in Healthy Volunteers

ABSTRACT Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, penicillin- and quinolone-resistant Streptococcus pneumoniae, and vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. The safety, tolerability, and pharmacokinetics of nemonoxacin were investigated in a double-blind, ascending-single-dose study involving 56 healthy subjects (48 males and 8 females) who were randomly assigned to 1 of 7 dose cohorts. In each successive cohort, two subjects received a placebo and six received single oral doses of 25, 50, 125, 250, 500, 1,000, or 1,500 mg nemonoxacin. Nemonoxacin was well tolerated up to the maximum dose of 1,500 mg. No severe or serious adverse events were observed. The most frequent adverse events were contact dermatitis, pruritus, and erythema. No clinically significant abnormalities were noted in the electrocardiograms, vital signs, or laboratory tests. The plasma concentrations increased over the dose range, and at 500 mg, the free area under the plasma concentration-time curve/MIC90 ratios and free maximum nemonoxacin concentration/MIC90 ratios against drug-sensitive/drug-resistant S. pneumoniae and S. aureus were greater than 227 and 24, respectively. The peak time and elimination half-life of nemonoxacin were 1 to 2 h and 9 to 16 h, respectively. The oral clearance was approximately 0.22 liter/h/kg. The plasma protein binding was approximately 16%. The results of this study support further evaluation of the multiple-dose safety, tolerability, and pharmacokinetics of nemonoxacin.

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Tonabersat, a Gap-Junction Modulator: Efficacy and Safety in Two Randomized, Placebo-Controlled, Dose-Ranging Studies of Acute Migraineceph

Cephalalgia ◽

10.1111/j.1468-2982.2009.01974.x ◽

2009 ◽

Vol 29 (2_suppl) ◽

pp. 17-27 ◽

Cited By ~ 31

Author(s):

SD Silberstein ◽

J Schoenen ◽

H Göbel ◽

HC Diener ◽

AH Elkind ◽

...

Keyword(s):

Adverse Events ◽

North American ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Plasma Concentrations ◽

International Study ◽

Maximum Plasma ◽

Serious Adverse Events ◽

Double Blind ◽

Dose Ranging

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

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First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00969-19 ◽

2019 ◽

Vol 63 (11) ◽

Cited By ~ 3

Author(s):

Mammen P. Mammen ◽

Danielle Armas ◽

Frank H. Hughes ◽

Andrew M. Hopkins ◽

Cindy L. Fisher ◽

...

Keyword(s):

Adverse Events ◽

Phase 1 ◽

Safety Data ◽

Healthy Adults ◽

Antifungal Drug ◽

Renal Elimination ◽

Serious Adverse Events ◽

Dose Escalation Study ◽

Double Blind ◽

Time Curve

ABSTRACT VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal in vitro activity, and potent in vivo activity against Aspergillus fumigatus, including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study, was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (i.v.) doses of VL-2397. All dosing cohorts were fully enrolled; all subjects completed the safety follow-up. A safety committee reviewed the safety data for each dosing cohort prior to recommending the initiation of each subsequent cohort. No serious adverse events (SAEs) occurred; the majority of treatment-emergent adverse events (TEAEs) were mild and self-limited. The most common drug-related TEAEs were infusion site reactions. No clinically concerning trends were noted in vital signs, electrocardiograms, physical examinations, or safety laboratory results. Following single infusions of VL-2397, the overall and maximum exposures rose less than proportionally with increasing doses from 3 mg to 1,200 mg as indicated by area under the concentration-time curve over 24 h (AUC24) and maximum concentration (Cmax). No signs of VL-2397 accumulation were observed following i.v. infusions of 300, 600, and 1,200 mg every 24 h (q24h) for 7 days. Renal elimination played a major role in total body clearance, with up to 47% of unmetabolized drug in urine 24 h after administration at single doses of >30 mg. Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK, and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis.

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Open-Label, Dose Escalation Study of the Safety and Pharmacokinetic Profile of Tefibazumab in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.3.959-962.2005 ◽

2005 ◽

Vol 49 (3) ◽

pp. 959-962 ◽

Cited By ~ 20

Author(s):

Sandra Reilley ◽

Eric Wenzel ◽

Laurie Reynolds ◽

Beth Bennett ◽

Joseph M. Patti ◽

...

Keyword(s):

Healthy Volunteers ◽

Dose Escalation ◽

Maximum Concentration ◽

Dose Range ◽

Plasma Concentrations ◽

Open Label ◽

Serious Adverse Events ◽

Dose Escalation Study ◽

Label Dose ◽

The Mean

ABSTRACT Tefibazumab (Aurexis) is a humanized monoclonal antibody being evaluated as adjunctive therapy for the treatment of Staphylococcus aureus infections. This open-label, dose escalation study evaluated the safety and pharmacokinetics of tefibazumab in 19 healthy volunteers aged 18 to 69 years. Each subject received a single administration of tefibazumab at a dose of 2, 5, 10, or 20 mg/kg of body weight infused over 15 min. Plasma samples for pharmacokinetic assessments were obtained before infusion as well as 1, 6, 12, and 24 h and 3, 4, 7, 21, 28, 42, and 56 days after dosing. Plasma concentrations of tefibazumab were detected 1 h after the end of the infusion, with a mean maximum concentration of drug in serum (C max) of 59, 127, 252, and 492 μg/ml following doses of 2, 5, 10, and 20 mg/kg, respectively. The median time to maximum concentration of drug in serum (T max) was 1.0 h for each dose. The mean elimination half-life (t 1/2) was approximately 22 days. The volume of distribution (V) was 4.7, 6.7, 7.2, and 7.2 liters after doses of 2, 5, 10, and 20 mg/kg, respectively. Clearance (CL) was 6.0, 9.2, 10.2, and 9.9 ml/hr, respectively. At the highest dose, plasma levels of tefibazumab were >100 μg/ml for 21 days. On day 56, the mean plasma concentrations were 6.3, 10.0, 16.4, and 30.5 μg/ml for the 2, 5, 10, and 20 mg/kg doses, respectively. Tefibazumab exhibited linear kinetics across doses of 5, 10, and 20 mg/kg. No anti-tefibazumab antibodies were detected after dosing in any subject. There were no serious adverse events, and tefibazumab was well tolerated over the entire dose range.

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Safety, Tolerability and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02329-20 ◽

2021 ◽

Author(s):

J. T. Guptill ◽

S. M. Raja ◽

V. C. Juel ◽

E. B. Walter ◽

M Cohen-Wolkowiez ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Adverse Events ◽

Clinical Laboratory ◽

Human Study ◽

Post Exposure Prophylaxis ◽

Serious Adverse Events ◽

Dose Escalation Study ◽

Double Blind ◽

Time Curve ◽

Post Exposure

Objective Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given post-exposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. Methods This double-blind, single-center, placebo-controlled dose escalation study, randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at pre-specified time points for PK and immunogenicity analyses. Results Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life >20 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent anti-drug antibody responses in the low and middle dosing groups and none at the highest dose. Interpretation NTM-1632 is well-tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and post-exposure prophylaxis.

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Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease

Thrombosis and Haemostasis ◽

10.1160/th16-10-0815 ◽

2017 ◽

Vol 117 (11) ◽

pp. 2026-2033 ◽

Cited By ~ 6

Author(s):

Detlef Albrecht ◽

Mintu Turakhia ◽

Daniel Ries ◽

Thomas Marbury ◽

William Smith ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Adverse Events ◽

Plasma Concentrations ◽

Anticoagulation Therapy ◽

Serious Adverse Events ◽

Single Dose Study ◽

Cyp2c9 Genotype ◽

The Difference ◽

Repeated Dosing

AbstractChronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t 1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.

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Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00717-19 ◽

2019 ◽

Vol 63 (9) ◽

Cited By ~ 4

Author(s):

Nadine G. Rouphael ◽

Selwyn J. Hurwitz ◽

Mari Hart ◽

Allison Beck ◽

Evan J. Anderson ◽

...

Keyword(s):

Adverse Events ◽

Clinical Laboratory ◽

Subcutaneous Tissue ◽

Phase 1 ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Plasma Exposure ◽

Serious Adverse Events ◽

Double Blind ◽

Time Curve

ABSTRACT Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro. (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.)

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Stimulation of Platelet Production in Healthy Volunteers by a Novel Pegylated Peptide-Based Thrombopoietin (TPO) Receptor Agonist.

Blood ◽

10.1182/blood.v106.11.1249.1249 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1249-1249 ◽

Cited By ~ 10

Author(s):

Dirk Cerneus ◽

K. Brown ◽

R. Harris ◽

D. End ◽

C. Molloy ◽

...

Keyword(s):

Adverse Events ◽

Receptor Agonist ◽

Dose Range ◽

Plasma Concentrations ◽

Blood Levels ◽

Post Dose ◽

Serious Adverse Events ◽

Platelet Production ◽

Platelet Counts

Abstract A novel, pegylated, peptide-based thrombopoietin receptor agonist (peg-TPOmp) was shown to possess in vitro and in vivo thrombopoietic activity. In cell-based assays, peg-TPOmp was active at picomolar concentrations. In vivo, peg-TPOmp increased platelet production dose-dependently in rats (ED50 single i.v. dose ~ 100 μg/kg), dogs and mice. A phase I study was conducted in healthy male volunteers to investigate the tolerability, PD and PK of peg-TPOmp. Forty volunteers were randomized to receive peg-TPOmp or placebo as a single i.v. bolus injection in a ratio of 6:2. The peg-TPOmp dose range explored was 0.375, 0.75, 1.5, 2.25 or 3 μg/kg. PK analysis indicated dose-related kinetics of peg-TPOmp, although at doses of 0.75 μg/kg or lower, plasma concentrations were generally below the LOQ of 6.25 ng/mL. Mean Cmax values ranged from 11 ng/mL for 0.75 μg/kg to 62 ng/mL at 3.0 μg/kg. The mean terminal half-life ranged from approx. 18 to 36 hours. Platelet counts increased dose-dependently reaching peak levels at Day 10–12, and counts returned to baseline within 3–4 weeks. Mean peak platelet levels ranged from 315 x109/L at 0.375 μg/kg to 685 x 109/L at 3 μg/kg. Mean increase of peak platelet counts from baseline ranged from 1.4-fold at 0.375 μg/kg to 3.2-fold at 3.0 μg/kg. Endogenous TPO levels dose-dependently increased, reaching peak levels at 3 days post-dose, possibly due to a reduced rate of clearance. No significant changes were observed in blood levels of IL-6, IL-11 and EPO levels. Platelet function, assessed as collagen-induced platelet aggregation in whole blood, was not different between the treatments. None of the subjects experienced serious adverse events or dose-limiting toxicities. The most frequently observed adverse events included mild headache and fatigue and occurred both after active treatment and placebo. No antibodies against peg-TPOmp were detected. Based on the safety, PK and PD data, peg-TPOmp shows promise as an agent to treat thrombocytopenic disorders.

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A Randomized, Double-Blind, Single-Dose Study Comparing the Biosimilarity of HOT-1010 With Bevacizumab (Avastin®) in Chinese Healthy Male Subjects

Frontiers in Pharmacology ◽

10.3389/fphar.2021.694375 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kai Huang ◽

Linling Que ◽

Ying Ding ◽

Nannan Chu ◽

Zhenzhong Qian ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Geometric Mean ◽

Enzyme Linked Immunosorbent Assay ◽

Pharmacokinetic Parameters ◽

Healthy Male ◽

Serious Adverse Events ◽

Double Blind ◽

Single Dose Study ◽

Male Subjects

Objective: This study was conducted to compare the pharmacokinetics, safety and immunogenicity of HOT-1010 with bevacizumab (Avastin®) in Chinese healthy male subjects.Methods: A single-center, randomized, double-blind, single-dose, parallel trial was performed in 84 Chinese healthy male subjects who randomly (1:1) received a single intravenous infusion of 1 mg/kg HOT-1010 or Avastin® for 90 min and followed up for 85 days. Serum concentrations of bevacizumab were analyzed by enzyme-linked immunosorbent assay. Primary pharmacokinetic parameters, Cmax, AUC0-t and AUC0-∞, were calculated and evaluated the bioequivalence between HOT-1010 and Avastin®, the safety and immunogenicity of investigational drugs were also assessed.Results: A total of 82 subjects completed the study. The 90% Confidence Intervals for geometric mean ratios of Cmax, AUC0-t and AUC0-∞ were 91.81–103.64%, 85.19–95.39% and 85.04–95.36%, which were all within the bioequivalence margin. Treatment-emergent adverse events were reported in 27 (65.9%) subjects in HOT-1010 group and 23 (56.1%) subjects in Avastin® group. Most TEAEs were mild or moderate. No TEAEs, Serious Adverse Events or deaths leading to discontinuation was reported. Subjects were all tested negative for Anti-drug Antibody.Conclusion: HOT-1010 exhibited the similar pharmacokinetics, safety and immunogenicity profiles of bevacizumab (Avastin®) in Chinese healthy male subjects.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/index.html, CTR20181610.

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Safety and Immunogenicity of a Novel Staphylococcus aureus Vaccine: Results from the First Study of the Vaccine Dose Range in Humans

Clinical and Vaccine Immunology ◽

10.1128/cvi.00356-10 ◽

2010 ◽

Vol 17 (12) ◽

pp. 1868-1874 ◽

Cited By ~ 40

Author(s):

Clayton Harro ◽

Robert Betts ◽

Walter Orenstein ◽

Eun-Jeong Kwak ◽

Howard E. Greenberg ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Immune Response ◽

Adverse Events ◽

Immune Responses ◽

Geometric Mean ◽

Dose Range ◽

Vaccine Dose ◽

Double Blind Study ◽

Mean Concentration ◽

Positive Immune Response

ABSTRACT Merck V710 is a novel vaccine containing the conserved Staphylococcus aureus iron surface determinant B shown to be protective in animal models. A phase I, multicenter, double-blind study of the dose range was conducted to assess the immunogenicity and safety of an adjuvanted liquid formulation of V710. A total of 124 adults (18 to 55 years of age) were randomized 1:1:1:1 to receive one 0.5-ml intramuscular injection of V710 (5 μg, 30 μg, or 90 μg) or saline placebo. A positive immune response was defined as at least a 2-fold increase in IsdB-specific IgG levels from baseline levels. Local and systemic adverse events were assessed for 5 and 14 days, respectively, following vaccination. Positive immune responses were detected in 12 (67%) of the 18 subjects in the groups receiving 30 and 90 μg V710 tested at day 10. At day 14, a significantly greater proportion of subjects manifested a positive immune response with higher geometric mean concentrations in the V710 30-μg (86%; geometric mean concentration of 116 μg/ml) and 90-μg (87%; geometric mean concentration of 131 μg/ml) dose groups than in the V710 5-μg (29%; geometric mean concentration of 51 μg/ml) or placebo (4%; geometric mean concentration of 23 μg/ml) groups. Immune responses were durable through day 84. Subjects <40 and ≥40 years of age had comparable immune responses. The most common adverse events were injection-site pain, nausea, fatigue, and headache, usually of mild intensity. No immediate reactions or serious adverse events were reported. In this first study of V710 in humans, a single 30-μg or 90-μg dose was more immunogenic than the 5-μg dose or placebo. Immune responses were evident by 10 to 14 days after vaccination in most responders.

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Adverse events and blinding in two randomized trials of hyperbaric oxygen for persistent post-concussive symptoms

Undersea and Hyperbaric Medicine ◽

10.22462/13.15.2019.10 ◽

2019 ◽

pp. 331-340

Author(s):

Susan Churchill ◽

◽

Kayla Deru ◽

Lindell K. Weaver ◽

Steffanie H. Wilson ◽

...

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Hyperbaric Oxygen ◽

Gas Flow ◽

Randomized Trials ◽

Symptom Improvement ◽

Sham Control ◽

Serious Adverse Events ◽

Double Blind ◽

To Receive

Safety monitoring and successful blinding are important features of randomized, blinded clinical trials. We report chamber- and protocol-related adverse events (AEs) for participants enrolled in two randomized, double-blind clinical trials of hyperbaric oxygen (HBO2) for persistent post-concussive symptoms clinicaltrials.gov identifiers NCT01306968, HOPPS, and NCT01611194, BIMA), as well as the success of maintaining the blind with a low-pressure sham control arm. In both studies, participants were randomized to receive HBO2 (1.5 atmospheres absolute, >99% oxygen) or sham chamber sessions (1.2 atmospheres absolute, room air). In 143 participants undergoing 4,245 chamber sessions, chamber-related adverse events were rare (1.1% in the HOPPS study, 2.2% in the BIMA study). Minor, non-limiting barotrauma was the most frequently reported. Rarely, some participants experienced headache with chamber sessions. No serious adverse events were associated with chamber sessions. An allocation questionnaire completed after intervention revealed that the sham control arm adequately protected the blind in both trials. Participants based allocation assumptions on symptom improvement or lack of symptom improvement and could not discern intervention arm by pressure, smell, taste, or gas flow.

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