Gabapentin Treatment for Alcohol Dependence.


A Randomized Clinical Trial

Importance  Approved medications for alcohol dependence are prescribed for less than 9% of US alcoholics.

Objective  To determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid–modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner.

Design, Participants and Setting  A 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital.

Interventions  Oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling.

Main Outcomes and Measures  Rates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study.

Results  Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups.

Conclusions and Relevance  Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence.

Soure: JAMA

Add-on Eslicarbazepine Reduces Partial-Onset Seizures.


Once-daily adjunctive therapy with eslicarbazepine significantly reduced the frequency of partial-onset seizures in adult patients compared with adding a placebo, and the effect was sustained out to 1 year. In an analysis of pooled data from 3 phase-3 pivotal trials, doses of 800 mg and 1200 mg were well tolerated.

Eslicarbazepine is an oral drug that stabilizes the inactive state of voltage-gated sodium channels and blocks T-type voltage-gated calcium channels.

Patrício Soares-da-Silva, MD, PhD, head of research and development at BIAL in S. Mamede do Coronado, Portugal, the developer of the drug, presented trial results here at the XXI World Congress of Neurology (WCN).

The 3 trials had slight variations in protocols, but in general involved an 8-week observation or single-blind drug period, 2 weeks of drug titration depending on dose, a 12-week double-blind maintenance period, 4 weeks of tapering of the drug or not, and an open-label extension period. Two trials (BIA-2093-301 and 302) tested the drug at 400 mg, 800 mg, or 1200 mg daily or placebo for the maintenance period, with about 100 patients in each group. Trial BIA-2093-303 dropped the 400-mg dose (about 84 patients per group).

The pooled groups were well matched for mean age (about 37 years), sex (half were men), seizure types, duration of epilepsy (22 years), and the number of concomitant antiepileptic drugs (AEDs) they were taking. About 70% of patients in each group were receiving 2 other AEDs besides the trial drug.

Dr. Soares-da-Silva said that eslicarbazepine significantly reduced the seizure frequency in each 4-week period of the 12-week double-blind maintenance phase from 8.17 ± 0.034 with placebo (n = 279) to 6.24 ± 0.034 with 800 mg (n = 262) and to 5.95 ± 0.035 with 1200 mg (n = 253) (both P < .001 vs placebo), the primary endpoint of the trials.

The responder rate, defined as a 50% or greater reduction in seizure frequency over the 12-week period, rose from 21.5% with placebo to 36.3% with 800 mg of eslicarbazepine and 43.5% with 1200 mg.

Positive Results Continue to 1 Year

Of 857 patients completing the double-blind period, 833 entered the open-label extension phase, and 612 (73.5%) completed the full year, with a median daily dose of 800 mg. The maximum allowed dose was 1200 mg.

The drug maintained its efficacy during the open-label extension period and showed a slight rise in both the responder rate and the proportion of patients free of seizures.

Table. Eslicarbazepine Efficacy During 1-year Extension Period*

Time Period

Responder Rate (%)

Proportion of Seizure-Free Patients (%)

Weeks 5 to 16

46.1

6.3

Weeks 17 to 28

47.0

9.4

Weeks 29 to 40

48.2

10.1

Weeks 41 to 52

50.1

13.6

*Median eslicarbazepine dose was 800 mg.

 

Treatment with adjunctive eslicarbazepine was associated with improvements in mood and quality of life, as assessed by QOLIE-31 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Whether patients had mild, moderate, or severe symptoms, all those who improved had improved significantly at the final assessment compared with baseline (all P < .001).

On the basis of the results of the pivotal trials, Dr. Soares-da-Silva said the European Medicines Agency approved eslicarbazepine for use in Europe as adjunctive therapy for adults with partial-onset seizures. It has not been approved in the United States, but he noted it is now undergoing trials in the United States as monotherapy.

Monotherapy Trials

Topline results of 2 phase 3 monotherapy trials of eslicarbazepine were just reported by Sunovion Pharmaceuticals. In both trials the drug met the primary endpoints.

Treatment was well tolerated and demonstrated seizure control rates superior to those among historical controls in adult patients with partial-onset seizures with or without secondary generalization who were not well controlled with current antiepileptic drugs, a statement from Sunovion released September 17 notes.

The agent is under review by the US Food and Drug Administration (FDA) as a once-daily adjunctive therapy for partial-onset seizures in patients aged 18 years or older with epilepsy.

“Pending the outcome of FDA review of the current New Drug Application (NDA) resubmission for eslicarbazepine acetate as an adjunctive treatment, Sunovion plans to submit these data as part of a supplemental NDA in support of a monotherapy indication,” Fred Grossman, DO, senior vice president, clinical development and medical affairs at Sunovion, said in the company’s statement.

The phase 3 studies, dubbed 093-045 and 093-046, were double-blind, historical-controlled, randomized trials with identical designs. Study 093-045 included 193 patients from 67 study centers in North America, and study 093-046 included 172 patients from 41 centers in 5 countries.

The primary endpoint of both studies was the proportion of patients meeting predefined exit criteria, “signifying worsening seizure control,” the statement notes, 16 weeks after titration compared with historical controls.

In both studies, adults with partial-onset seizures that were not well controlled, defined as 4 or more partial-onset seizures in the 8 weeks before screening and no 4-week seizure-free period, with 1 to 2 AEDs, were gradually converted to monotherapy treatment with eslicarbazepine. They were then randomly assigned in a 1:2 ratio to receive 1200 or 1600 mg of eslicarbazepine daily.

Detailed results from the 2 monotherapy studies will be presented at upcoming scientific meetings, the company notes.

Difference Debated?

Asked to comment about what eslicarbazepine may add to the AED armamentarium as adjunctive therapy, session chair Reeta Kälviäinen, MD, from the Kuopio Epilepsy Center, and professor of clinical epileptology at the University of Eastern Finland in Kupio, told Medscape Medical News that it is something of a debate at the moment whether eslicarbazepine differs significantly from oxcarbazepine.

“It’s a metabolite of oxcarbazepine, and we think at the moment that it might have a little bit less adverse effects than oxcarbazepine, less hyponatremia and less idiosynchrous reactions,” she said. “And we hope that therefore it would be better tolerated, perhaps as carbamazepine, as effective as oxcarbazepine, and then you can dose it once daily, which is a benefit.”

She said that she was “a little bit disappointed” that the study did not show which AEDs eslicarbazepine might be best used with but that current studies and clinical practice may reveal the better combinations. But for now, “definitely you shouldn’t add it on top of other sodium channel blockers. That’s not the way to use it,” because of additive adverse effects.

Similarly, if a patient has problems while receiving carbamazepine or oxcarbazepine, switching to eslicarbazepine would be a bad idea. “It’s nearly the same drug, so that’s a dangerous situation. So that’s a contraindication,” Dr. Kälviäinen noted. She said clinicians are now “a little bit mixed up” in choosing among these similar drugs, and clearer studies on the differences among them are needed.

Otto Muzik, PhD, a professor of radiology and pediatrics at Wayne State Medical School in Detroit, Michigan, questioned the value of adding another drug in this same class.

“It’s still not approved in the States, and it appears to me that the FDA does not believe that there is added value,” he mentioned to Medscape Medical News. “So that means that…it’s probably going to do better than a placebo, but if you now say, ‘Give me the best combined therapy of drugs,’ and now we throw in this new drug, is it more efficacious or not, and the jury seems to be still out on that.”

Medication May Help Treat Cocaine Addiction For The First Time.


Photo credit: Drug Enforcement Administration

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There are no current FDA-approved medications for cocaine addiction, but that might be about to change. A new study published in JAMA Psychiatry from researchers at University of Virginia’s Department of Psychiatry and Neurobehavioral Sciences has shown that cocaine dependence can be treated with the repurposed medication topiramate.

Topiramate (trade name Topamax) is an anticonvulsant that has been used to treat a variety of conditions, such as seizures associated with epilepsy and Lennox-Gastaut syndrome, bipolar disorder, alcohol dependance, and migraine prevention.

The double-blind study consisted of 142 individuals addicted to cocaine. Half of the group was randomly assigned to receive topiramate while the other half was given a placebo. Over the course of the 12 weeks for the study, the topiramate group reported significantly more cocaine-free days which indicate the likelihood of cocaine-free weeks. Additionally, the topiramate group reported fewer cravings and increased functioning when compared to the placebo group.

Side effects were mild and minimal, including inattentiveness, skin tingling, taste distortions, and decreased appetite. High doses of topiramate have been associated with glaucoma, though that was not a factor in this study. Ultimately, the results of the study suggest that topiramate is a safe and effective drug for combatting cocaine dependence.

Because topiramate has been shown to be effective in cocaine and alcohol addictions, head researcher Bankole A. Johnson is optimistic that understanding how the chemicals interact with the brain could help scientists understand the neurobiological cause of addiction.

Cocaine, a derivative of the South American coca plant, causes more emergency room visits than any other illegal substance. Cocaine is an intense stimulator of the central nervous system and affects the circulatory system by increasing heart rate while constricting blood vessels. Cocaine use can lead to stroke or cardiac arrest, which may cause death.

– See more at: http://www.iflscience.com/health-and-medicine/medication-may-help-treat-cocaine-addiction-first-time#sthash.OxWhdhZb.dpuf

GH replacement could delay progression of chronic HF.


New preliminary data demonstrate that growth hormone replacement therapy improved exercise and cardiac performance of patients with chronic heart failure and growth hormone deficiency.

Antonio Cittadini, MD, and colleagues conducted a single-blind study to investigate whether patients with both chronic heart failure (HF) and GH deficiency assigned GH replacement therapy could experience delays in the progression of chronic HF.

The findings suggest that “correction of [growth hormone] deficit improves exercise and cardiac performance of [chronic HF] patients in an enduring way,” the researchers wrote.

The researchers screened participants from a previous controlled, single blind, single-center study for GH deficiency. Of the 158 participants screened, 63 had GH deficiency and 56 were subsequently enrolled in the trial. Twenty-eight patients were randomly assigned standard therapy for chronic HF plus subcutaneous somatropin (rDNA origin; Saizen, Merck-Serono) at a dose of 0.012 mg/kg every second day. The other 28 patients were assigned standard therapy for chronic HF alone.

Follow-up was 4 years, and 17 patients in the GH group and 14 in the control group completed the study. The primary endpoint was peak oxygen consumption (VO2) because “it is a strong, independent predictor of [chronic HF] progression,” according to the study background. Peak VO2 improved in the GH group over 4 years, but not in the control group. The treatment effect was 7.1 ± 0.7 mL/kg/min in the GH group, which beat the researchers’ projected improvement of 4 mL/kg/min, vs. –1.8 ± 0.5 mL/kg/minin the control group (P<.001).

LV ejection fraction increased by 10 ± 3% in the growth-hormone group, but decreased by 2 ± 5% in the control group (P<.001). LV end-systolic volume index decreased by 22 ± 6 mL/m2 in the growth-hormone group and increased by 8 ± 3 ml/m2 in the control group (P<.001).

“The improvements in LV end-systolic volume and ejection fraction were [as] equally relevant [as improvements in peak VO2]; both are consolidated predictors of survival,” Cittadini and colleagues wrote.

The only adverse events reported by the GH group were two cases of arthralgia.

Given the limitations of a small study of this design with a large dropout rate, the association should be studied further in a large, multicenter, placebo-controlled, double blind trial, according to the researchers.

Source: Endocrine Today

A Randomized, Double-Blind, Controlled Trial Comparing Rifaximin Plus Lactulose With Lactulose Alone in Treatment of Overt Hepatic Encephalopathy. .


Hepatic encephalopathy (HE) is associated with poor prognosis in cirrhosis. Drugs used in the treatment of HE are primarily directed at the reduction of the blood ammonia levels. Rifaximin and lactulose have shown to be effective in HE. We evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE.

METHODS:In this prospective double-blind randomized controlled trial, 120 patients with overt HE were randomized into two groups: (group A lactulose plus rifaximin 1,200 mg/day; n=63) and group B (lactulose (n=57) plus placebo). The primary end point was complete reversal of HE and the secondary end points were mortality and hospital stay.
RESULTS:A total of 120 patients (mean age 39.4+/-9.6 years; male/female ratio 89:31) were included in the study. 37 (30.8%) patients were in Child-Turcotte-Pugh (CTP) class B and 83 (69.2%) were in CTP class C. Mean CTP score was 9.7+/-2.8 and the MELD (model for end-stage liver disease) score was 24.6+/-4.2. At the time of admission, 22 patients (18.3%) had grade 2, 40 (33.3%) had grade 3, and 58 (48.3%) had grade 4 HE. Of the patients, 48 (76%) in group A compared with 29 (50.8%) in group B had complete reversal of HE (P<0.004). There was a significant decrease in mortality after treatment with lactulose plus rifaximin vs. lactulose and placebo (23.8% vs. 49.1%, P<0.05). There were significantly more deaths in group B because of sepsis (group A vs. group B: 7:17, P=0.01), whereas there were no differences because of gastrointestinal bleed (group A vs. group B: 4:4, P=nonsignificant (NS)) and hepatorenal syndrome (group A vs. group B: 4:7, P=NS). Patients in the lactulose plus rifaximin group had shorter hospital stay (5.8+/-3.4 vs. 8.2+/-4.6 days, P=0.001).
CONCLUSION:Combination of lactulose plus rifaximin is more effective than lactulose alone in the treatment of overt HE.

Source: American  Journal  Gastroenterology

 

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy..


To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial.

METHODS: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters.
RESULTS: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA).
CONCLUSIONS: This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. CLASSIFICATION OF EVIDENCE: This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.

Source: Neurology

Nitrous oxide for early analgesia in the emergency setting: a randomized, double-blind multicenter prehospital trial..


Although 50% nitrous oxide (N(2) O) and oxygen is a widely used treatment, its efficacy had never been evaluated in the prehospital setting. The objective of this study was to demonstrate the efficacy of premixed N(2) O and oxygen in patients with out-of-hospital moderate traumatic acute pain.

METHODS: This prospective, randomized, multicenter, double-blind trial enrolled patients with acute moderate pain (numeric rating scale [NRS] score between 4 and 6 out of 10) caused by trauma. Patients were assigned to receive either 50/50 N(2) O and oxygen 9 L/min (N(2) O group) or medical air (MA) 9 L/min (MA group), in ambulances from two nurse-staffed fire department centers. After the first 15 minutes, every patient received N(2) O and oxygen. The primary endpoint was pain relief at 15 minutes (T15), defined as a NRS
RESULTS: Sixty patients were included with no differences between groups in age (median = 34 years, interquartile range [IQR] = 23 to 53 years), sex (37 males, 66%), and initial median NRS of 6 (IQR = 5 to 6). At T15, 67% of the patients in the N(2) O group had an NRS score of 3 or lower versus 27% of those in the MA group (delta = 40%, 95% confidence interval [CI] = 17% to 63%; p < 0.001). The median pain scores were lower in the N(2) O group at T15, 2 (IQR = 1 to 4) versus 5 (IQR = 3 to 6). There was a difference at 5 minutes that persisted at all subsequent time points. Four patients (one in the N(2) O group) experienced adverse events (nausea) during the protocol.
CONCLUSIONS: This study demonstrates the efficacy of N(2) O for the treatment of pain from acute trauma in adults in the prehospital setting.

Source: Acad Emerg Med.

 

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial.


Abstract

Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.

Design Double blind randomised trial.

Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.

Participants Patients aged ≥1 year admitted to hospital with confirmed severe influenza.

Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).

Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.

Results Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.

Conclusions There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.

Discussion

In this large randomised controlled trial of antiviral treatment in patients with severe influenza we found that double dose oseltamivir was well tolerated but did not confer additional virological or clinical benefits over standard dose treatment in patients in South East Asia. There were no differences between the treatment arms in detection of viral RNA or infectious virus on day five, and there were also no differences in clinical failure rates, mortality in hospital, or rates of adverse events between the dose regimens on day five. We enrolled a heterogeneous population that included mostly children and also those infected with avian H5N1 or H1N1-pdm09 viruses. While subgroup analyses based on age cohorts, virus type and subtype, and time to treatment did not suggest additional virological efficacy of double dose oseltamivir in any subgroup, these results should be interpreted with caution as the study was not powered for these analyses.

Our patients presented relatively late after the onset of illness, a median of five days overall (seven days for H5N1). Despite administration of oseltamivir, about 30% of those enrolled remained positive for viral RNA (the primary endpoint) after five days of treatment. Timing of oseltamivir treatment is important as several studies have shown that early treatment confers greater virological and clinical benefits.4 5 6 32 33 34 In particular, later viral clearance has been noted with delayed treatment with oseltamivir compared with treatment within two to three days after onset of symptoms in observational reports from patients with H1N1-pdm09, especially those with severe illness.35 36 37 38 39 40 In the current trial, 73 (22.4%) patients presented within three days of illness, but even in this subpopulation, double dose oseltamivir was not associated with more rapid viral RNA clearance. Over a quarter of patients received neuraminidase inhibitors before enrolment, which could have influenced the effect size and contributed to the low proportion of patients shedding virus at day five in both treatment groups.

Although viral RNA detection in samples from the upper respiratory tract might not accurately reflect viral replication in the lower respiratory tract, especially in those with severe illness,39 prolonged viral RNA detection in upper respiratory tract samples has been shown to correlate with inpatient morbidity and prolonged hospital stay. In our study viral detection on day five was observed at about twofold the frequency in those meeting the criteria for clinical failure, although lack of clinical failure was not a surrogate for cessation of viral detection. Thus in our study the delays in starting treatment with oseltamivir also probably contributed to the substantial rates of admission to intensive care (18%), use of supplemental oxygen (30%), mechanical ventilation (12%), and mortality in hospital of 6.4%. Although our study was not placebo controlled for ethical reasons, other studies indicate that early oseltamivir treatment in people with severe influenza is associated with both clinical benefits and more rapid viral clearance from upper respiratory tract samples.

Possible reasons for findings

It is unclear why double dose oseltamivir does not seem to offer benefit over standard dose in patients with severe influenza. Blood trough concentrations of oseltamivir carboxylate from 75 mg or 150 mg twice daily in influenza exceed the IC50 (inhibitory concentration) of influenza viruses.42 43 Inhibition of viral neuraminidase by oseltamivir might be a saturable process, and maximal inhibition might be achieved with a standard dose; exceeding these concentrations might not produce an additional clinical or virological effect. In this regard, a randomised oseltamivir controlled study of intravenous peramivir (BioCryst Pharmaceuticals, Durham, NC), which reaches over 20-fold higher peak blood concentrations of active metabolite than oseltamivir carboxylate, found similar viral reductions in patients with influenza A virus admitted to hospital.44 Further studies of peramivir and other intravenous neuraminidase inhibitors currently in progress should provide additional evidence regarding this hypothesis.

Infection with avian H5N1 virus, higher baseline viral load, and severity of disease were independently associated with longer viral RNA detection. The association between avian H5N1, severe illness, and prolonged shedding has been well described.14 The clearance kinetics of influenza viruses, both without antiviral treatment and with oseltamivir treatment,32 41 could explain longer viral RNA detection with higher baseline viral loads. It is unclear whether the independent association with disease severity might be related to impaired mechanisms of viral clearance or higher intrinsic rates of viral replication or both in these patients. Severe chronic comorbidities are seen commonly in industrialised countries and are related to prolonged viral shedding but most of our patients lacked these comorbidities.40 41

The heterogeneous population characteristics, geographical differences in recruitment (most patients were from Vietnam but there were no significant differences between Vietnam and other sites), and the variety of infecting viruses in our trial reflect the clinical circumstances in South East Asia during our study but might be viewed as a limitation. Most of these patients were children and had low or normal BMI, and for all patients only about a fifth reported a chronic underlying medical condition. Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology. We did not have many adults in our study and results were inconclusive but indicate no difference in efficacy between the two oseltamivir regimens. We would caution the extension of our results to, for example, morbidly obese adults with severe influenza and those who could have underlying chronic illnesses. We conducted several statistical comparisons and inevitably subgroup analyses involved small numbers; thus power was limited and some significant results could have resulted by chance. Additionally, as all patients were randomised to an active treatment, our study was not designed to evaluate the efficacy of oseltamivir in severe influenza nor in H5N1 infections. This large randomised trial did, however, examine an important clinical and public health question and showed a lack of a clinical or virological benefit of double dose compared with standard dose oseltamivir in patients admitted to hospital with severe influenza. Our results and other observational reports from avian H5N110 and H1N1-pdm0911 36 infections do not support routine use of double dose oseltamivir to treat severe influenza. These findings have implications for both clinical management and pandemic preparedness including during the current H7N9 epidemic.16 17 18

What is already known on this topic

  • Clinical trials in patients with uncomplicated influenza have shown that treatment with oseltamivir has clinical and virological benefit when administered within 48 hours of onset of symptoms
  • Observational studies in severe influenza have shown that oseltamivir treatment, if given early, is associated with reduced mortality and shorter length of hospital stay. Reduced mortality has also been reported for patients with H5N1 influenza treated with oseltamivir
  • Several authorities have suggested the use of double dose oseltamivir for severe influenza, although there is no clinical evidence to support this
  • In the largest randomised trial on the treatment of severe influenza, no clinical or virological benefit of double dose oseltamivir over standard dose was found
  • These findings have implications for both clinical management of severe influenza and for pandemic preparedness of emerging influenza viruses including the current H7N9 epidemic

What this study adds

 

 

Source: BMJ

 

 

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial.


Abstract

Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.

Design Double blind randomised trial.

Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.

Participants Patients aged ≥1 year admitted to hospital with confirmed severe influenza.

Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).

Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.

Results Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.

Conclusions There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.

Discussion

In this large randomised controlled trial of antiviral treatment in patients with severe influenza we found that double dose oseltamivir was well tolerated but did not confer additional virological or clinical benefits over standard dose treatment in patients in South East Asia. There were no differences between the treatment arms in detection of viral RNA or infectious virus on day five, and there were also no differences in clinical failure rates, mortality in hospital, or rates of adverse events between the dose regimens on day five. We enrolled a heterogeneous population that included mostly children and also those infected with avian H5N1 or H1N1-pdm09 viruses. While subgroup analyses based on age cohorts, virus type and subtype, and time to treatment did not suggest additional virological efficacy of double dose oseltamivir in any subgroup, these results should be interpreted with caution as the study was not powered for these analyses.

Our patients presented relatively late after the onset of illness, a median of five days overall (seven days for H5N1). Despite administration of oseltamivir, about 30% of those enrolled remained positive for viral RNA (the primary endpoint) after five days of treatment. Timing of oseltamivir treatment is important as several studies have shown that early treatment confers greater virological and clinical benefits.4 5 6 32 33 34 In particular, later viral clearance has been noted with delayed treatment with oseltamivir compared with treatment within two to three days after onset of symptoms in observational reports from patients with H1N1-pdm09, especially those with severe illness.35 36 37 38 39 40 In the current trial, 73 (22.4%) patients presented within three days of illness, but even in this subpopulation, double dose oseltamivir was not associated with more rapid viral RNA clearance. Over a quarter of patients received neuraminidase inhibitors before enrolment, which could have influenced the effect size and contributed to the low proportion of patients shedding virus at day five in both treatment groups.

Although viral RNA detection in samples from the upper respiratory tract might not accurately reflect viral replication in the lower respiratory tract, especially in those with severe illness,39 prolonged viral RNA detection in upper respiratory tract samples has been shown to correlate with inpatient morbidity and prolonged hospital stay. In our study viral detection on day five was observed at about twofold the frequency in those meeting the criteria for clinical failure, although lack of clinical failure was not a surrogate for cessation of viral detection. Thus in our study the delays in starting treatment with oseltamivir also probably contributed to the substantial rates of admission to intensive care (18%), use of supplemental oxygen (30%), mechanical ventilation (12%), and mortality in hospital of 6.4%. Although our study was not placebo controlled for ethical reasons, other studies indicate that early oseltamivir treatment in people with severe influenza is associated with both clinical benefits and more rapid viral clearance from upper respiratory tract samples.4 8 14 36 37 38 39 40 41

Possible reasons for findings

It is unclear why double dose oseltamivir does not seem to offer benefit over standard dose in patients with severe influenza. Blood trough concentrations of oseltamivir carboxylate from 75 mg or 150 mg twice daily in influenza exceed the IC50 (inhibitory concentration) of influenza viruses.42 43 Inhibition of viral neuraminidase by oseltamivir might be a saturable process, and maximal inhibition might be achieved with a standard dose; exceeding these concentrations might not produce an additional clinical or virological effect. In this regard, a randomised oseltamivir controlled study of intravenous peramivir (BioCryst Pharmaceuticals, Durham, NC), which reaches over 20-fold higher peak blood concentrations of active metabolite than oseltamivir carboxylate, found similar viral reductions in patients with influenza A virus admitted to hospital.44 Further studies of peramivir and other intravenous neuraminidase inhibitors currently in progress should provide additional evidence regarding this hypothesis.

Infection with avian H5N1 virus, higher baseline viral load, and severity of disease were independently associated with longer viral RNA detection. The association between avian H5N1, severe illness, and prolonged shedding has been well described.14 The clearance kinetics of influenza viruses, both without antiviral treatment and with oseltamivir treatment,32 41 could explain longer viral RNA detection with higher baseline viral loads. It is unclear whether the independent association with disease severity might be related to impaired mechanisms of viral clearance or higher intrinsic rates of viral replication or both in these patients. Severe chronic comorbidities are seen commonly in industrialised countries and are related to prolonged viral shedding but most of our patients lacked these comorbidities.40 41

The heterogeneous population characteristics, geographical differences in recruitment (most patients were from Vietnam but there were no significant differences between Vietnam and other sites), and the variety of infecting viruses in our trial reflect the clinical circumstances in South East Asia during our study but might be viewed as a limitation. Most of these patients were children and had low or normal BMI, and for all patients only about a fifth reported a chronic underlying medical condition. Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology. We did not have many adults in our study and results were inconclusive but indicate no difference in efficacy between the two oseltamivir regimens. We would caution the extension of our results to, for example, morbidly obese adults with severe influenza and those who could have underlying chronic illnesses. We conducted several statistical comparisons and inevitably subgroup analyses involved small numbers; thus power was limited and some significant results could have resulted by chance. Additionally, as all patients were randomised to an active treatment, our study was not designed to evaluate the efficacy of oseltamivir in severe influenza nor in H5N1 infections. This large randomised trial did, however, examine an important clinical and public health question and showed a lack of a clinical or virological benefit of double dose compared with standard dose oseltamivir in patients admitted to hospital with severe influenza. Our results and other observational reports from avian H5N110 and H1N1-pdm0911 36 infections do not support routine use of double dose oseltamivir to treat severe influenza. These findings have implications for both clinical management and pandemic preparedness including during the current H7N9 epidemic.16 17 18

What is already known on this topic

  • Clinical trials in patients with uncomplicated influenza have shown that treatment with oseltamivir has clinical and virological benefit when administered within 48 hours of onset of symptoms
  • Observational studies in severe influenza have shown that oseltamivir treatment, if given early, is associated with reduced mortality and shorter length of hospital stay. Reduced mortality has also been reported for patients with H5N1 influenza treated with oseltamivir
  • Several authorities have suggested the use of double dose oseltamivir for severe influenza, although there is no clinical evidence to support this
  • In the largest randomised trial on the treatment of severe influenza, no clinical or virological benefit of double dose oseltamivir over standard dose was found
  • These findings have implications for both clinical management of severe influenza and for pandemic preparedness of emerging influenza viruses including the current H7N9 epidemic

What this study adds

 

Source: BMJ

 

Different antibiotic treatments for group A streptococcal pharyngitis.


Antibiotics provide only modest benefit in treating sore throat, although effectiveness increases in participants with positive throat swabs for group A beta-haemolytic streptococci (GABHS). It is unclear which antibiotic is the best choice if antibiotics are indicated.

OBJECTIVES: To assess the evidence on the comparative efficacy of different antibiotics in: (a) alleviating symptoms (pain, fever); (b) shortening the duration of the illness; (c) preventing relapse; and (d) preventing complications (suppurative complications, acute rheumatic fever, post-streptococcal glomerulonephritis). To assess the evidence on the comparative incidence of adverse effects and the risk-benefit of antibiotic treatment for streptococcal pharyngitis. SEARCH
METHODS: We searched CENTRAL 2012, Issue 10, MEDLINE (1966 to October week 2, 2012), EMBASE (1974 to October 2012) and Web of Science (2010 to October 2012).
SELECTION CRITERIA: Randomised, double-blind trials comparing different antibiotics and reporting at least one of the following: clinical cure, clinical relapse, complications, adverse events.
DATA COLLECTION AND ANALYSIS: Two authors independently screened trials for inclusion and extracted data.
MAIN RESULTS: Seventeen trials (5352 participants) were included; 16 compared with penicillin (six with cephalosporins, six with macrolides, three with carbacephem and one with sulfonamides), one trial compared clindamycin and ampicillin. Randomisation reporting, allocation concealment and blinding were poor.There was no difference in symptom resolution between cephalosporins and penicillin (intention-to-treat (ITT) analysis; N = 5; n = 2018; odds ratio for absence of resolution of symptoms (OR) 0.79, 95% confidence interval (CI) 0.55 to 1.12). Clinical relapse was lower with cephalosporins (N = 4; n = 1386; OR 0.55, 95% CI 0.31 to 0.99; overall number needed to treat to benefit (NNTB) 50), but found only in adults (OR 0.42, 95% CI 0.20 to 0.88; NNTB 33). There were no differences between macrolides and penicillin. Carbacephem showed better symptom resolution post-treatment (N = 3; n = 795; OR 0.70, 95% CI 0.49 to 0.99; NNTB 14), but only in children (N = 2; n = 233; OR 0.57, 95% CI 0.33 to 0.99; NNTB 8.3). Children experienced more adverse events with macrolides (N = 1, n = 489; OR 2.33; 95% CI 1.06 to 5.15).
AUTHORS’ CONCLUSIONS: Evidence is insufficient to show clinically meaningful differences between antibiotics for GABHS tonsillopharyngitis. Limited evidence in adults suggests cephalosporins are more effective than penicillin for relapse, but the NNTB is high. Limited evidence in children suggests carbacephem is more effective for symptom resolution. Data on complications are too scarce to draw conclusions. Based on these results and considering the low cost and absence of resistance, penicillin can still be recommended as first choice.

Source: Cochrane database