Controlled Trial of a 5-Day Course of Telithromycin versus Doxycycline for Treatment of Mild to Moderate Scrub Typhus

ABSTRACT New antibiotics are required to have the antibacterial activity against doxycycline-resistant Orientia tsutsugamushi. An in vitro sensitivity study showed that telithromycin was more effective than erythromycin for Rickettsia, Bartonella, and Coxiella burnetii. In this prospective, open-label, randomized trial, we enrolled patients with mild-to-moderate scrub typhus. We compared the efficacy and safety of a 5-day telithromycin therapy with those of a 5-day doxycycline therapy at Chosun University Hospital or one of its two community-based affiliated hospitals (Jangheung Hospital and Cheomdan Hospital), which are all located in southwestern Korea, between September and December 2005. A total of 92 patients were randomly assigned to either the telithromycin group (n = 47) or the doxycycline group (n = 45). After the treatment, fever control time was 20.45 ± 12.9 h in the telithromycin group and 22.60 ± 21.44 h in the doxycycline group (P > 0.05). After the treatment, the cure rate was 100% in the telithromycin group and 97.8% in the doxycycline group (P > 0.05). Furthermore, there were no significant differences in time elapsed until such symptoms as headache, myalgia, and rash disappeared. No serious adverse events or death were noted following the treatment in both groups. There were no significant differences in adverse events. In conclusion, the efficacy and safety of a 5-day once-a-day regimen of 800 mg telithromycin were equivalent to those of a 5-day twice-a-day regimen of 100 mg doxycycline in patients with mild-to-moderate scrub typhus. Telithromycin could be considered a promising new antibacterial agent for patients with scrub typhus.

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Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211873 ◽

2017 ◽

Vol 76 (12) ◽

pp. 2065-2070 ◽

Cited By ~ 33

Author(s):

Lisa K Stamp ◽

Peter T Chapman ◽

Murray Barclay ◽

Anne Horne ◽

Christopher Frampton ◽

...

Keyword(s):

Adverse Events ◽

Dose Escalation ◽

Controlled Trial ◽

Serum Urate ◽

Extension Study ◽

Open Label ◽

Serious Adverse Events ◽

Open Label Extension ◽

Randomised Controlled ◽

Kidney Impairment

ObjectivesTo determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout.MethodsPeople, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24.ResultsThe mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups.ConclusionsThe majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment.Trial registration numberACTRN12611000845932

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NE-180, a Novel glycoPEGylated Erythropoietin Demonstrates Dose-Dependent Activity in a Phase 1 Single Dose, Dose Escalating Study in Normal Human Volunteers (NHV).

Blood ◽

10.1182/blood.v108.11.1149.1149 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1149-1149

Author(s):

Bruce A. Wallin ◽

Denise Ramjit ◽

Michael Seiberling ◽

David Zopf

Keyword(s):

Adverse Events ◽

Animal Studies ◽

Phase 1 ◽

Stopping Rules ◽

Open Label ◽

Serious Adverse Events ◽

Maximal Increase ◽

The Mean ◽

Dose Dependent

Abstract NE-180 is a glycoPEGylated recombinant human erythropoietin that binds to and activates the erythropoietin (EPO) receptor. It has demonstrated in vitro activities comparable to EPO and an extended serum half-life in animal studies. This may allow less frequent dosing in patients being treated with chronic anemia. METHODS: A single center, open-label study of NE-180, administered as single escalating doses given by the SC or IV route, was conducted to assess the safety, tolerability, PK and PD. Subjects (male or female NHV) were planned to be assigned to one of 4 dose groups, 10 subjects per dose with 5 SC and 5 IV subjects per group: 0.5, 1.5, 3, or 4.5 mg/kg. Each dose group was planned to be initiated in an ascending, sequential fashion unless or until stopping rules were met. RESULTS: 25 NHV (16 females) were enrolled in the first two dose cohorts and have completed 56 day follow-up. The 1.5 mg/kg IV cohort met the protocol-specified Hb rate of rise stopping rule (change in Hb greater than 1 g/dL during any 14 day period). Injections were generally well tolerated with no discontinuations for adverse events or serious adverse events. Reticulocyte increases were dose proportional. Average reticulocyte count at baseline was 1.0±0.3%. The maximal increase occurred at day 7. The mean change from baseline for the 0.5 and 1.5 mg/kg SC group was: 0.9±0.4% and 2.2±0.9%, respectively. The mean change from baseline for the 0.5 and 1.5 mg/kg IV group was: 1.7±0.8% and 2.3±0.8%, respectively. PK data will be presented. CONCLUSIONS: Single doses up to 1.5 mg/kg of NE-180 administered to NHV were generally well tolerated and demonstrated potent dose-dependent erythropoietic activity.

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EFFICACY AND SAFETY OF ADALIMUMAB IN ANKYLOSING SPONDYLITIS: DATA FROM REAL LIFE

Romanian Journal of Rheumatology ◽

10.37897/rjr.2015.1.7 ◽

2015 ◽

Vol 24 (1) ◽

pp. 44-49

Author(s):

Claudiu Popescu ◽

◽

Cristina Coroama ◽

Costin Mitulescu ◽

Denisa Predeteanu ◽

...

Keyword(s):

Ankylosing Spondylitis ◽

Adverse Events ◽

Clinical Setting ◽

Demyelinating Disease ◽

Real Life ◽

Time Frame ◽

University Hospital ◽

Controlled Trials ◽

Efficacy And Safety ◽

Serious Adverse Events

Rationale. Data from controlled trials showed that adalimumab, a humanized anti-TNF monoclonal antibody, is effective and safe in the treatment of ankylosing spondylitis (AS). Objectives. The present study aimed to observe the effi cacy and safety of adalimumab in AS in a real life clinical setting. Methods. The study observed cross-sectionaly and retrospectively the efficacy and safety of adalimumab in all the patients admitted to the Rheumatology Department of “Sfânta Maria” Clinical Hospital between January 2008 and June 2013 who were classified as having AS according to the modified New York criteria. The diagnosis and follow-up of uveitic cases were done in the Ophthalmology Department of the Emergency University Hospital. Results. Within the study time-frame, 79 AS patients met the inclusion criteria: 71 (89.9%) had adalimumab for at least 24 months; 8 (10.1%) switched from adalimumab to another biological, as follows: 3 (3.8%) because of serious adverse events, 3 (3.8%) were primary non-responders and 2 (2.5%) were secondary non-responders. The clinical response was fast: after 3 months of treatment, 59 (83.1%) patients had BASDAI < 4 and 55 (77.5%) patients had BASFI < 4. Regarding safety, the serious adverse effects recorded were: infectious arthritis, pulmonary tuberculosis, pulmonary sarcoidosis. There were no cases of cancer or demyelinating disease during the study frame. Conclusions. Therapy with adalimumab in AS produces a prompt and lasting effect. The efficacy (remission) and safety (adverse events) of adalimumab can be monitored in the real-life clinical setting using BASDAI, BASFI, and routine clinical evaluations. Clinicians may need to expect a slightly higher rate of serious adverse events and rate of treatment discontinuation than those reported by controlled trials.

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A Moxifloxacin-based Regimen for the Treatment of Recurrent, Drug-sensitive Pulmonary Tuberculosis: An Open-label, Randomized, Controlled Trial

Clinical Infectious Diseases ◽

10.1093/cid/ciz152 ◽

2019 ◽

Vol 70 (1) ◽

pp. 90-98 ◽

Cited By ~ 1

Author(s):

Rubeshan Perumal ◽

Nesri Padayatchi ◽

Nonhlanhla Yende-Zuma ◽

Anushka Naidoo ◽

Dhineshree Govender ◽

...

Keyword(s):

Adverse Events ◽

Absolute Risk ◽

Controlled Trial ◽

Treatment Success ◽

Control Group ◽

Open Label ◽

Serious Adverse Events ◽

Conversion Rates ◽

Significant Difference ◽

Culture Conversion

Abstract Background The substitution of moxifloxacin for ethambutol produced promising results for improved tuberculosis treatment outcomes. Methods We conducted an open-label, randomized trial to test whether a moxifloxacin-containing treatment regimen was superior to the standard regimen for the treatment of recurrent tuberculosis. The primary and secondary outcomes were the sputum culture conversion rate at the end of 8 weeks and the proportion of participants with a favorable outcome, respectively. Results We enrolled 196 participants; 69.9% were male and 70.4% were co-infected with human immunodeficiency virus (HIV). There was no significant difference between the study groups in the proportion of patients achieving culture conversion at the end of 8 weeks (83.0% [moxifloxacin] vs 78.5% [control]; P = .463); however, the median time to culture conversion was significantly shorter (6.0 weeks, interquartile range [IQR] 4.0–8.3) in the moxifloxacin group than the control group (7.9 weeks, IQR 4.0– 11.4; P = .018). A favorable end-of-treatment outcome was reported in 86 participants (87.8%) in the moxifloxacin group and 93 participants (94.9%) in the control group, for an adjusted absolute risk difference of −5.5 (95% confidence interval −13.8 to 2.8; P = .193) percentage points. There were significantly higher proportions of participants with Grade 3 or 4 adverse events (43.9% [43/98] vs 25.5% [25/98]; P = .01) and serious adverse events (27.6% [27/98] vs 12.2% [12/98]; P = .012) in the moxifloxacin group. Conclusions The replacement of ethambutol with moxifloxacin did not significantly improve either culture conversion rates at the end of 8 weeks or treatment success, and was associated with a higher incidence of adverse events. Clinical Trials Registration NCT02114684.

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Management of hard-to-heal leg ulcers with an acid-oxidising solution versus standard of care: the MACAN study

Journal of Wound Care ◽

10.12968/jowc.2021.30.9.694 ◽

2021 ◽

Vol 30 (9) ◽

pp. 694-704

Author(s):

Robert Strohal ◽

Martina Mittlböck ◽

Werner Müller ◽

Gilbert Hämmerle

Keyword(s):

Wound Healing ◽

Adverse Events ◽

Controlled Trial ◽

Standard Of Care ◽

Size Reduction ◽

Wound Dressings ◽

Leg Ulcers ◽

Open Label ◽

Serious Adverse Events ◽

Wound Size

Objective: The efficacy of available wound dressings in the treatment of hard-to-heal wounds is limited. A new therapeutic approach using an acid-oxidising solution (AOS) was developed. Its effect on healing progress, tolerability and safety properties were investigated in a clinical study, and compared with standard of care (SOC) wound dressings. The study aimed to demonstrate the non-inferiority of AOS to SOC in terms of wound healing progress. Method: This open-label, randomised controlled trial was conducted at two study centres in Austria with patients with either infected or non-infected hard-to-heal leg ulcers of different aetiology. Patients were treated for six weeks either with AOS or SOC wound dressings. Outcome assessments included the percentage of granulation and re-epithelialisation tissue, wound size reduction, changes in wound pH, infection control and wound pain, local tolerability and adverse events (AEs). Healing time and rate were also assessed. Results: A total of 50 patients took part. In the AOS group, wounds exhibited higher amounts of granulation and re-epithelialisation tissue, and a faster and more pronounced wound size reduction compared with wounds in the SOC group. In the AOS-treated versus SOC-treated patients, a greater percentage of complete healing of hard-to-heal ulcers was achieved by the end of the study period (32% versus 8%, respectively). Furthermore, the wound pH decreased significantly faster in these wounds (p<0.0001). In all patients with infected leg ulcers, local infection was overcome more rapidly under AOS treatment. In the AOS group, one AE and no serious adverse events (SAEs) were detected versus 24 AEs and two SAEs in the SOC group. Conclusion: In this study, AOS proved to be a highly effective treatment to support wound healing in infected or non-infected hard-to-heal leg ulcers of different aetiology. Efficacy was found to be not only non-inferior but superior to SOC wound dressings. Furthermore, tolerability and safety profiles were favourable for AOS.

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Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944) in the Treatment of Patients with Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02095-16 ◽

2017 ◽

Vol 61 (6) ◽

Cited By ~ 21

Author(s):

William O'Riordan ◽

Courtney Tiffany ◽

Nicole Scangarella-Oman ◽

Caroline Perry ◽

Mohammad Hossain ◽

...

Keyword(s):

Adverse Events ◽

Clinical Utility ◽

The United States ◽

Phase 2 ◽

Efficacy And Safety ◽

Open Label ◽

Gram Positive ◽

Double Blind ◽

Skin Structure

ABSTRACT Gepotidacin is a novel, first-in-class, triazaacenaphthylene antibacterial agent which has in vitro activity against causative pathogens of acute bacterial skin and skin structure infections (ABSSSIs). This phase 2, randomized, 2-part, multicenter, dose-ranging, response-adaptive study with optional intravenous-oral switch evaluated the efficacy and safety of gepotidacin for the treatment of Gram-positive ABSSSIs in 122 adult patients in the United States. The study had a double-blind phase (part 1; intravenous [750 mg or 1,000 mg every 12 h {q12h}]) and an open-label phase (part 2; intravenous [750 mg q12h, 1,000 mg q12h, or 1,000 q8h]). The primary endpoint was a composite of efficacy and safety which consisted of the early cure rate and the withdrawal rate due to drug-related adverse events and utilized a clinical utility index for dose selection. At the early efficacy visit (48 to 72 h after the first dose), the 750-mg q12h and 1,000-mg q8h groups met prespecified success criteria for clinical utility in terms of efficacy and safety; however, the 1,000-mg q12h group did not meet these criteria due to observed lower efficacy rates. The most frequently reported adverse events were nausea (20%) and diarrhea (13%). These encouraging phase 2 results demonstrate the potential for gepotidacin to meet the medical need for novel antibacterial agents to treat ABSSSIs due to drug-resistant pathogens through a unique mechanism of action. (This study has been registered at ClinicalTrials.gov under registration no. NCT02045797.)

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A randomized phase II trial of efficacy and safety of the immunotherapy ALECSAT as an adjunct to radiotherapy and temozolomide for newly diagnosed glioblastoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab156 ◽

2021 ◽

Author(s):

Katja Werlenius ◽

Giuseppe Stragliotto ◽

Michael Strandeus ◽

Malin Blomstrand ◽

Helena Carén ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Phase Ii Trial ◽

Performance Status ◽

Progression Free Survival ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Open Label ◽

Serious Adverse Events ◽

Significant Difference

Abstract Background There is an urgent need for effective treatments against glioblastoma (GBM). In this trial we investigated the efficacy and safety of an adoptive cell-based immunotherapy. Methods Patients with newly diagnosed GBM were recruited at four study sites in Sweden. The patients were randomized 1:2 to receive either radiotherapy (RT), 60 Gy/30 fractions, with concomitant and adjuvant temozolomide (TMZ) only, or RT and TMZ with addition of Autologous Lymphoid Effector Cells Specific Against Tumor (ALECSAT) in an open-label phase II trial. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were survival and safety of ALECSAT. Results Sixty-two patients were randomized to either RT and TMZ alone (n=22) or RT and TMZ with ALECSAT (n=40). Median age was 57 years (range 38-69), 95% of the patients were in good performance status (WHO 0-1). There was no significant difference between the study arms (SOC vs. ALECSAT + SOC) in PFS (7.9 vs. 7.8 months; HR 1.28; 95% CI 0.70, 2.36; P=0.42), or in median overall survival (OS) (18.3 vs. 19.2 months; HR 1.16, 95% CI 0.58, 2.31; P=0.67). The treatment groups were balanced in terms of serious adverse events (52.4% vs. 52.5%), but adverse events ≥ grade 3 were more common in the experimental arm (81.0% vs. 92.5%). Conclusion Addition of ALECSAT immunotherapy to standard treatment with radiochemotherapy was well tolerated but did not improve PFS or OS for patients with newly diagnosed GBM.

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Early use of nitazoxanide in mild Covid-19 disease: randomised, placebo-controlled trial

European Respiratory Journal ◽

10.1183/13993003.03725-2020 ◽

2020 ◽

pp. 2003725

Author(s):

Patricia R. M. Rocco ◽

Pedro L. Silva ◽

Fernanda F. Cruz ◽

Marco Antonio C. M. Junior ◽

Paulo F. G. M. M. Tierno ◽

...

Keyword(s):

Viral Load ◽

Adverse Events ◽

Controlled Trial ◽

Nasopharyngeal Swab ◽

Serious Adverse Events ◽

Double Blind ◽

Symptom Resolution ◽

Days Of Therapy ◽

Secondary Outcomes

Nitazoxanide is widely available and exerts broad-spectrum antiviral activity in vitro. However, there is no evidence of its impact on SARS-CoV-2 infection. In a multicenter, randomised, double-blind, placebo-controlled trial, adult patients presenting up to 3 days after onset of Covid-19 symptoms (dry cough, fever, and/or fatigue) were enrolled. After confirmation of SARS-CoV2 infection by RT-PCR on a nasopharyngeal swab, patients were randomised 1:1 to receive either nitazoxanide (500 mg) or placebo, TID, for 5 days. The primary outcome was complete resolution of symptoms. Secondary outcomes were viral load, laboratory tests, serum biomarkers of inflammation, and hospitalisation rate. Adverse events were also assessed. From June 8 to August 20, 2020, 1575 patients were screened. Of these, 392 (198 placebo, 194 nitazoxanide) were analysed. Median time from symptom onset to first dose of study drug was 5 (4–5) days. At the 5-day study visit, symptom resolution did not differ between the nitazoxanide and placebo arms. Swabs collected were negative for SARS-CoV-2 in 29.9% of patients in the nitazoxanide arm versus 18.2% in the placebo arm (p=0.009). Viral load was also reduced after nitazoxanide compared to placebo (p=0.006). The percent viral load reduction from onset to end of therapy was higher with nitazoxanide (55%) than placebo (45%) (p=0.013). Other secondary outcomes were not significantly different. No serious adverse events were observed. In patients with mild Covid-19, symptom resolution did not differ between nitazoxanide and placebo groups after 5 days of therapy. However, early nitazoxanide therapy was safe and reduced viral load significantly.

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An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with castrate-resistant prostate cancer (CRPC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.5062 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 5062-5062

Author(s):

G. R. MacVicar ◽

A. Greco ◽

J. Reeves ◽

J. Maleski ◽

J. Holmlund ◽

...

Keyword(s):

Adverse Events ◽

Phase 1 ◽

Single Agent ◽

Safety Data ◽

Preliminary Evidence ◽

Open Label ◽

Serious Adverse Events ◽

Vein Thrombosis

5062 Background: Antiapoptotic Bcl-2 family proteins are overexpressed in CRPC and contribute to resistance to therapy. The oral pan-Bcl-2 inhibitor AT-101 (Bcl-2, Bcl-XL, Bcl-W, Mcl-1) is active as a single agent and in combination in in vitro and in vivo tumor models and as a single agent in CRPC. The Phase 1 portion of the study determined the recommended dose for phase II to be D (75mg/m2 q3weeks) in combination with P (5mg b.i.d. on days 1–21), and AT-101 at 40mg b.i.d. on days 1–3 of each 21-day cycle, and was previously reported. Methods: Men ≥18 years of age with chemotherapy-naïve CRPC (N = 36). Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: 36 patients (pts) have been enrolled in the study. Twenty-four (67%) pts achieved a partial response (PR) (>50% PSA decline), and 26 (72%) pts treated had at least a 30% decrease in PSA level. Nine of 19 pts (47%) with measurable disease had a PR. One PR was unconfirmed per RECIST. Thirteen pts (36%) completed >10 cycles of therapy (range 2–24) thus far. Four pts remains active. Safety data is available for 31 pts. The most common (>20%) Adverse Events (AEs) include: fatigue (68%), nausea (52%), diarrhea (45%), alopecia (32%), constipation and dysgeusia (26%), and neutropenia and vomiting (26%). Neutropenia was the only gr. 4 event occurring in more than one pt (3pts). Serious Adverse Events (SAEs) considered related were reported in 5 pts (16%). The only SAEs reported in 2 or more pts were urinary tract infection (3 pts) and deep vein thrombosis (2 pts) and none were considered related. No ileus has been reported. Conclusions: AT-101 when given in combination with D/P is well tolerated and shows preliminary evidence of efficacy in pts with CRPC. A randomized trial is ongoing. [Table: see text]

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Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results

Multiple Sclerosis Journal ◽

10.1177/1352458509357065 ◽

2009 ◽

Vol 16 (2) ◽

pp. 197-207 ◽

Cited By ~ 108

Author(s):

G. Comi ◽

P. O'Connor ◽

X. Montalban ◽

J. Antel ◽

E-W. Radue ◽

...

Keyword(s):

Multiple Sclerosis ◽

Adverse Events ◽

Controlled Trial ◽

Phase Iii ◽

Initial Increase ◽

Efficacy And Safety ◽

Serious Adverse Events ◽

T2 Lesions ◽

Study Programme ◽

Large Phase

In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS). The objectives were to monitor the 36-month, interim efficacy and safety results of the ongoing extension of this study. In the extension (months 7—36), placebo-treated patients were re-randomized to either dose of fingolimod; fingolimod-treated patients continued at the same dose. During months 15—24, all patients receiving fingolimod 5.0 mg switched to 1.25 mg. Of the 250 patients who entered the extension study, 173 (69%) continued to month 36. Most patients were free from gadolinium-enhanced lesions (88—89%) or new T2 lesions (70—78%) at month 36. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20—0.21, and 68—73% remained relapse-free at month 36. Over 36 months, nasopharyngitis (34%), headache (30%), fatigue (19%) and influenza (18%) were the most commonly reported adverse events. Pulmonary function remained stable and blood pressure was stable after an initial increase (3—5 mmHg) during the first 6 months of fingolimod treatment; serious adverse events included infections and skin cancer. The low MRI and clinical disease activity at 6 months were maintained at 36 months with fingolimod, which was generally well tolerated by most patients. The efficacy and safety of oral fingolimod are being further evaluated in a large phase III MS study programme.

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