Clinical Trials News

Hawaii Biotech Initiates Phase 1 Clinical Trial For Dengue Vaccine

2009-08-26T02:47:00.000-07:00

Hawaii Biotech, Inc. President and CEO Elliot Parks, Ph.D., announced that the company has initiated a Phase 1 clinical study with its monovalent dengue vaccine candidate. The double-blind, placebo controlled, dose escalation safety study in healthy subjects is being conducted at the St. Louis University Center for Vaccine Development. http://vaccine.slu.edu/ Vaccine recipients in this study will also be monitored for virus neutralizing antibodies.

"This dengue clinical study is an important milestone in Hawaii Biotech's maturation as a clinical stage company. In addition it confirms the versatility of our subunit vaccine technology platform," Parks notes. "This Phase 1 study will also prepare us for the initial clinical testing of Hawaii Biotech's tetravalent dengue vaccine."

Hawaii Biotech's dengue monovalent vaccine candidate is the first recombinant subunit vaccine for dengue to enter clinical studies. Previous dengue vaccine candidates tested in the clinic have been either live-attenuated or DNA-based vaccines. Hawaii Biotech intends to test a dengue tetravalent vaccine candidate, developed using the company's recombinant subunit vaccine technology, within a year.

The first phase of clinical development program is designed to assess safety, determine a dose range and identify potential side effects. Results from this clinical study are expected within a year.

Hawaii Biotech's dengue subunit vaccine candidate has been developed with financial assistance from the National Institutes of Health, the Department of Defense, and the Pediatric Dengue Vaccine Initiative.

About Dengue: Dengue, also known as "break-bone fever," is a prevalent infectious disease in tropical and subtropical countries throughout the world. Approximately 3.5 billion people live in endemic countries and about 100 million people are infected with dengue every year. Dengue infections result in an estimated 20,000 deaths. Dengue is caused by one of four closely related, but distinct, virus serotypes (DEN1, DEN2, DEN3, and DEN4), of the family Flaviviridae, which also includes yellow fever, West Nile, Japanese encephalitis, and tick-borne encephalitis viruses. Dengue is transmitted by the bite of a mosquito infected with any one of the four dengue viruses. Infection with dengue virus results in severe flu-like symptoms that can lead to a life-threatening hemorrhagic fever. During the last quarter century, many tropical regions of the world have seen an increase in dengue cases. The southern United States is potentially susceptible to dengue epidemics as the types of mosquitoes that transmit dengue virus are prevalent there.

Source

50 Percent Of Healthcare Workers In Hong Kong Refuse To Get The Swine Flu Vaccine

2009-08-26T02:18:00.000-07:00

Research just published on bmj.com reports that about half of healthcare workers surveyed in Hong Kong say they would not be vaccinated against swine flu because of fears of side effects and doubts about effectiveness.

Still, the authors underline that vaccination is one of the most effective ways to reduce illness and death linked with pandemic flu. They believe that the benefits highly compensate for any possible risks.

The results of the research are unexpected, according to the authors, given SARS had such a huge impact in Hong Kong. Also, the study was underway at the same time as the World Health Organization (WHO) escalated its alert for swine flu to phase 5.

The results are comparable to a recent UK poll of almost 1,500 Nursing Times readers. It revealed that 30 percent of nurses said they would not have the swine flu vaccine.

The study documents that practically all countries with a pandemic flu plan intend to vaccinate healthcare workers as a priority group in order to protect the essential health infrastructure of their countries. However, this policy will only be successful if there is a high uptake of the vaccine.

Given the results of this study, lead author Professor Paul Chan from the Chinese University of Hong Kong mentions that a campaign to promote vaccination among healthcare workers is required.

Over 8,500 doctors, nurses, and related health professionals were surveyed. All were working at 31 hospital departments of internal medicine, pediatrics, and emergency medicine in Hong Kong.

Participants were initially surveyed from January to March 2009. This was when the WHO influenza pandemic alert was at phase 3. Then they were surveyed again in May 2009. At that point, the WHO raised its pandemic alert to phase 5 and it was the first time participants were specifically asked if they were willing to be vaccinated against swine flu. There was a response rate of 46.6 percent for the first survey and 48 percent for the second.

About 28 percent of respondents in the initial survey said they would be willing to be vaccinated against avian flu (H5N1).Interestingly, the authors explain, "no significant changes in the level of intention to accept pre-pandemic H5N1 vaccine were observed, despite the escalation to phase 5 because of the wide spread of H1N1 virus (swine flu)."

When the WHO alert level was at phase 5, 47.9 percent of respondents said they would be willing to be vaccinated against swine flu (H1N1).

The most frequent reasons for an intention to accept were:
• "wish to be protected"
• "following health authority's advice"

The most common reasons for refusal were:
• "worry about side effects"
• "query on the efficacy of the vaccine"
• "simply did not want the vaccine"
People who said they would accept the swine flu vaccination tended to be younger. They usually had received the seasonal flu vaccine in 2008-9 and feared they were more likely to get swine flu.

The authors write in conclusion: "To our knowledge, this is the largest study conducted to assess the willingness of healthcare workers to accept pre-pandemic influenza vaccination, and it provides important information on barriers to vaccination. Campaigns to promote vaccination should consider addressing the knowledge gap of staff and the specific target groups for intervention."

In an associated editorial, Rachel Jordan from the University of Birmingham and Andrew Hayward from the UCL Centre for Infectious Disease Epidemiology, emphasize that vaccination for healthcare workers is vital for their own protection and the safety of their patients. It could be of assistance to keep the NHS functioning at full capacity during the swine flu pandemic.

They claim that education and promotional campaigns alone have not been sufficient to convince healthcare workers to get vaccinated, "but the additional use of convenient mobile systems, monitoring and feedback systems, and the use of "opt-out" systems (where healthcare workers need to indicate their reasons for not accepting the vaccine) show promise."

30% of nurses 'don't want' flu jab

33,902 Swine Flu A(H1N1) Cases Including 170 Deaths In USA

2009-07-09T16:18:00.000-07:00

The Centers for Disease Control and Prevention (CDC) informed in its weekly update on Friday evening, 3rd July, 2009, that the total number of confirmed human cases of swine flu A(H1N1) infection stands at 33,902, including 170 deaths

In a Swine Flu conference held today in Cancun, Mexico, the World Health Organization (WHO) warned that the virus' spread is now "unstoppable". The WHO added that swine flu infection cases are mostly mild, with the vast majority of people recovering unaided.

Health authorities in the UK predict that British infection numbers should exceed 100,000 by the end of this summer

Effect Of Male Circumcision On The Prevalence Of High-Risk Human Papillomavirus In Young Men

2009-02-02T05:04:00.000-08:00

UroToday.com - Human papillomavirus is the most commonly sexually transmitted infection in the United States. The American Cancer Society estimates that about 11,000 women in the United States will be diagnosed with invasive cervical cancer annually and almost 4,000 will die from this disease. This study done by Dr. Bertran Auvert et al. investigated the association between male circumcision and the prevalence of human papillomavirus among young men.

This study utilized data from a trial conducted in Orange Farm, South Africa among men between the ages of 18-24 years. Urethral swabs were collected from participants in the intervention who were circumcised and the controls who were uncircumcised and were coming in for scheduled follow-up visits. Polymerase chain reactions were performed for analysis of human papillomavirus.

The prevalence of human papillomavirus was 14.8% in those that were circumcised and 22.3% in those who were uncircumcised. Controlling for other confounding variables such as ethnic group, age, education, sexual behavior [including condom use], marital status, and HIV showed no effect on the results.

The group concluded that this was the first randomized controlled trial to show a reduction in the prevalence of urethral human papillomavirus infection after circumcision. It correlates with the finding that women with a circumcised partner are at a lower risk of cervical cancer than women with uncircumcised partners.

Since human papillomavirus is a virus, HPV vaccines are being investigated. Currently, Gardasil is currently being administered for helping HPV prevention. Currently, only women are being treated with the HPV vaccine, but since both men and women are carriers of human papillomavirus, the possible benefits and efficacy of vaccinating men are currently being studied.

International Copper Industry Defines Role In The Fight Against Hospital Infections

2009-01-06T13:24:00.000-08:00

The copper industry is working together to answer one very important question: Can copper and copper alloys (brass and bronze) help curb the spread of bacteria that cause hospital infection? Results of laboratory testing and clinical trials indicate that they can. Scientists from around the world shared their work at the first world congress, 'Copper and Public Health', on copper's role in fighting the bacteria that cause hospital-acquired infections. The conference was held in Athens, Greece in November.

Leading scientists from the U.K., U.S., Germany and Greece, representing the disciplines of infection control, pathology, microbiology, hospital design, metallurgy and engineering, presented the scientific evidence supporting the case for incorporating copper surfaces into healthcare environments to help reduce the risk of infection and to protect public health. The first results from a clinical trial in Birmingham, England, demonstrate that the use of copper on certain surfaces on a busy hospital ward resulted in 90-100 percent fewer micro-organisms than the amount found on the control ward.

In the U.S., hospital-acquired infections claim the lives of some 100,000 people each year. The U.S. Copper Development Association (CDA) is taking a lead role in this international effort through two main initiatives: EPA registration of copper and copper alloys as antimicrobial and the initiation of clinical trials in three U.S. hospitals.

The EPA registration was granted based on independent laboratory tests demonstrating that copper, brass and bronze are more than 99.9 percent effective in killing specific disease-causing bacteria, including Methicillin-resistant Staphylococcus aureus (MRSA), one of the most virulent strains of antibiotic-resistant bacteria and a common cause of hospital- and community-acquired infections.

The clinical trials are comparing the amount of bacteria found on stainless steel, plastic and aluminum objects in intensive care units with the amount found on the same objects made of antimicrobial copper alloys, such as brass and bronze, in order to determine if copper alloys can lessen cross contamination, and perhaps lower rates of infection. The trials are funded by the U.S. Department of Defense under the aegis of the Telemedicine and Advanced Technologies Research Center (TATRC), a section of the Army Medical Research and Materiel Command (USAMRMC).

Promising New TB Drug Receives Phase 2 SBIR

2008-09-29T14:51:00.000-07:00

Sequella, Inc., a clinical-stage biopharmaceutical company focused on commercializing products to treat infectious diseases of epidemic potential, has announced that it received a $2.3 million, three-year Small Business Innovative Research (SBIR) grant from the National Institutes of Health (NIH),

National Institute of Allergy and Infectious Diseases (NIAID) for the development of SQ641, a promising new tuberculosis (TB) drug with potential to provide early and prolonged bacterial clearance during the intensive phase of TB treatment.

The Phase 2 SBIR grant will fund the conduct of several IND-related critical path studies, including delivery optimization in vivo.

Dr. Carol Nacy, CEO of Sequella said, "The NIH is a model example of how strong public/private partnerships help advance new infectious disease therapies into the drug pipeline and we thank them for this grant support. SQ641 is a potentially powerful antitubercular compound with a unique target of action. The SBIR grant award is scientific validation of our research and development efforts to identify important new drugs for diseases of concern to the global health community."

Results of the completed Phase 1 SBIR grant demonstrated that SQ641 has superior in vitro activity against Mycobacterium tuberculosis compared to all other TB drugs. It has a unique mechanism of action and a unique target, the translocase 1 (TL-1) enzyme, which is not the target of any existing antitubercular. In addition, SQ641 possesses exceptional activity against all members of the Mycobacteria family of bacteria, including M. tuberculosis, M. avium complex, and other pathogenic nontubercular Mycobacteria.

About SQ641

SQ641 is the lead drug candidate from a 7000-compound library of semi-synthetic TL-1 inhibitors developed as potential treatments for TB or bacterial pneumonia (Streptococcus pneumoniae). The compound inhibits TL-1, an enzyme required for cell wall synthesis in all bacteria, including Mycobacteria. Sequella licensed the compound library from Daiichi-Sankyo (November 2004). Daiichi-Sankyo identified the compound class and performed extensive research and preliminary preclinical development on several drug leads. Sequella has exclusive rights to the series of TL-1 inhibitors for the treatment of TB and all other indications for nearly every worldwide market.

What Is The Best Strategy For Treating Helicobacter Pylori?

2008-09-24T12:20:00.000-07:00

The most popular treatment for H pylori is triple therapy but resistance to Clarithromycin is reducing its effectiveness. Courses using four drugs have been known to be more successful but are used less popular because of their side-effects. While, what is the best way for treating H pylori-related diseases.
A research article to be published on 28 June 2008, in the World Journal of Gastroenterology addresses this question. The research team led by Prof. Mr Siok Ching from United Kingdom compared a lansoprazole-based triple versus quadruple therapy for H pylori eradication with emphasis on side effect profile, patient compliance and eradication rate at a rural district general hospital in Wales, United Kingdom.

Overall the treatment of H Pylori using both three drugs and four drugs are still highly effective in rural North Wales (92%), however, almost all (97%) of the patients who managed to complete the course of four tablets got rid of the infection.

Authors feel that treatments with four drugs remain the best option for white Caucasians in rural UK. Patients need educating about the side effects of the drugs and the reasons for treatment so that they can reap the full benefits.

They concluded that one-week triple and quadruple therapies have similar intention-to-treat eradication rates. Certain side effects are more common with quadruple therapy, which can compromise patient compliance. Patient education or modifications to the regimen are alternative options to improve compliance of the quadruple regimen.

The side effects may be reduced by replacing metronidazole with amoxycillin but patients should be better educated about the side effects in order to improve compliance and cure rates.

The Side Effects Of Monotherapy With Lamivudine

2008-09-24T12:19:00.000-07:00

Lamivudine has a high rate of antiviral resistance. Sequential anti-HBV treatment is commonly used for lamivudine resistance. We report 4 cases with rapid re-detection of HBV mutants during the lamivudine re-treatment.
The article was published in the World Journal of Gastroenterology. In this report, four patients received lamivudine as an initial treatment of HBV. They had adefovir and lamivudine as a rescue therapy consecutively. HBV-DNA level, YMDD mutations and adefovir -resistant mutations (RFMP) were tested every 3 mo during the sequential treatment. All the patients showed YMDD mutations during the initial lamivudine therapy. After adefovir therapy for lamivudine resistance, they showed viral breakthrough. Adefovir was switched to lamivudine, however, it did not induce viral suppression at all, rather increased in HBV-DNA with rapid re-emergence of the YMDD mutations. All the patients had ALT flares, and hepatic decompensation occurred in two patients. After switching to adefovir combined with entecavir or lamivudine for a rescue therapy, the patients had reduction in HBV-DNA and ALT improvement. These cases demonstrated that lamivudine re-treatment in patients with pre-exposed lamivudine resistance leads to rapid re-emergence of YMDD mutation with significant viral rebound and subsequent hepatic decompensation. Sequential administration of lamivudine with prior history of YMDD mutation should be abandoned.

The result suggests that lamivudine re-treatment in patients with pre-exposed lamivudine resistance leads to rapid re-emergence of YMDD mutation with significant viral rebound and subsequent hepatic decompensation. Sequential administration of lamivudine with prior history of YMDD mutation should be abandoned.

The study highlights that retreatment with lamivudine in patients with severe liver disease should be avoided.

FDA Approves GlaxoSmithKline's New Combination Vaccine For Children

2008-06-25T14:52:00.000-07:00

Image via WikipediaThe US Food and Drug Administration (FDA) announced yesterday that it had given approval for the first new combination vaccine for protecting 4 to 6 year old children against diphtheria, tetanus, pertussis and polio diseases in one shot, made by GlaxoSmithKline (GSK).

The vaccine is branded as the trademarked name KINRIX, and its official long name is Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine.

It is approved for use with children who have already received GSK's Infanrix or Pediarix combination vaccines. Infanrix covers DPT, diphtheria, tetanus and pertussis (whooping cough), and Pediarix covers DPT, hepatitis B and polio.

Health experts tend to recommend combination vaccines because they reduce the number of shots children receive in a single visit.

On Monday, Sanofi Pasteur, part of French drugmaker Sanofi-Aventis SA, announced that the FDA had granted a license for its new 5-in-1 vaccine for use with children under 5 to protect them against diptheria, tetanus, pertussis, polio and Hib disease.

Assistant Clinical Professor of Pediatrics, University of California, San Diego School of Medicine, Dr William P. Hitchcock said in a press statement that:

"Children 4 to 6 years-old can receive five or more vaccinations in a single visit, which can be stressful for parents and vaccinators."

Reducing the number of vaccine shots a child receives in a visit, combination vaccines like KINRIX may help families meet CDC recommendations and school vaccination requirements, he added.

According to GSK, clinical trial results on KINRIX showed that it offers similar protection to the separate vaccines for Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) and Inactivated Poliovirus (IPV), and it has a similar safety profile.

The Phase III trial of KINRIX was the final confirmation. This comprised a randomized controlled study involving 3,156 US children aged from 4 to 6 years who were vaccinated with KINRIX at the same time as receiving their second dose of measles, mumps and rubella (MMR) vaccine (US licensed M-M-RII).

All the children had already received four doses of DTaP (INFANRIX) and three doses of IPV (IPOL).

Director for US Clinical Research and Development/Medical Affairs at GlaxoSmithKline, Dr Wayde M Weston, said that KINRIX contains the same DTaP and IPV ingredients as INFANRIX and PEDIARIX, two vaccines that doctors in the US have used for many years.

"With the introduction of KINRIX," said Weston, "eligible 4 to 6 year-olds can receive protection against four serious diseases with one less shot."

Mycamine(R) (micafungin) Licensed For Use In Europe To Treat Serious Fungal Infections

2008-05-12T03:39:00.000-07:00

Image via WikipediaThe European Medicines Agency (EMEA) has announced the marketing authorisation of Mycamine®, Astellas Pharma Europe's treatment for invasive candidiasis, oesophageal candidiasis and prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell transplantation. Mycamine® will initially be available in the U.K and across the European market shortly after this.

Professor David Denning of The University of Manchester said of the announcement; "The approval of micafungin is very good news for patients with life-threatening fungal infections in Europe. The Company has conducted a number of large, high quality clinical studies in Candida infections with impressive results. Particularly welcome are the indications for fungal infections in children and babies, often a neglected group in the early drug approval process."

The efficacy and safety of Mycamine® have been demonstrated in a clinical development programme including more than 3,500 patients in 16 clinical trials. The trials included nearly 300 children. Mycamine® was launched in Japan in 2002 and in the US three years ago. In these two major markets more than 350,000 patients have been treated with the product.

"We are delighted that Mycamine® is now licensed for use in Europe." said Alan Houston, MBBS, MRCP, FFPM, Senior Vice President, Research and Development, Astellas Pharma Europe. "It means that doctors will now have a new option to treat both their adult and paediatric - including neonatal - patients with."

Recognising the increasing need for new products to fight the growing epidemic caused by healthcare associated infections, Astellas is committed to building a strong anti-infectives franchise. This is reflected by its extensive clinical trial programme which has been very positively received by key opinion leaders in the area.

Mycamine

The indications for adults, adolescents ≥ 16 years of age and elderly are: Treatment of invasive candidiasis; Treatment of oesophageal candidiasis in patients for whom intravenous therapy is appropriate; Prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count < 500 cells / μl) for 10 or more days. For children (including neonates) and adolescents <16 years of age, Mycamine is indicated for: Treatment of invasive candidiasis; Prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count < 500 cells / μl) for 10 or more days.

FDA Extends Review Timeline For Additional Indication For Antibiotic DORIBAX(TM)

2008-03-09T06:57:00.000-07:00

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., announced that the U.S. Food and Drug Administration (FDA) has extended the review timeline for the second New Drug Application for the antibiotic DORIBAX(TM) (doripenem for injection). The application, submitted in June 2007, seeks approval to market DORIBAX to treat nosocomial, or "hospital-acquired," pneumonia and ventilator-associated pneumonia, which occurs in patients who are on mechanical ventilation because they cannot breathe on their own.

The FDA extended the review period by three months to provide time for a full review of the application after receiving additional information it had requested from the company.

DORIBAX is already FDA-approved to treat complicated urinary tract and complicated intra-abdominal infections and is marketed by Ortho-McNeil(TM), Division of Ortho-McNeil-Janssen Pharmaceutical Services, Inc., in the U.S. The use of DORIBAX to treat complicated urinary tract and complicated intra-abdominal infections and nosocomial pneumonia, including ventilator-associated pneumonia, currently is under regulatory review in Europe, Canada and in other countries. DORIBAX is licensed from Shionogi & Co., Ltd.

INDICATIONS

DORIBAX is indicated as a single agent for the treatment of: complicated intra-abdominal infections caused by susceptible strains of E. coli, K. pneumoniae, P. aeruginosa, B. caccae, B. fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, S. intermedius, S. constellatus or P. micros, and for the treatment of complicated urinary tract infections, including pyelonephritis, caused by susceptible strains of E. coli, including cases with concurrent bacteremia, K. pneumoniae, P. mirabilis, P. aeruginosa, or A. baumannii.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORIBAX and other antibacterial drugs, DORIBAX should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting and modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

IMPORTANT SAFETY INFORMATION

DORIBAX is contraindicated in patients with known serious hypersensitivity to doripenem or other carbapenems or in patients who have demonstrated anaphylactic reactions to beta-lactams.

Serious and occasionally fatal hypersensitivity (anaphylactic) and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. If an allergic reaction to DORIBAX occurs, discontinue the drug. Serious acute anaphylactic reactions require emergency treatment with epinephrine and other emergency measures, including oxygen, IV fluids, IV antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.

Carbapenems may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations cannot be maintained in the therapeutic range or seizures occur.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two (2) months after administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

When DORIBAX has been used investigationally via inhalation, pneumonitis has occurred. DORIBAX should not be administered by this route.

Safety and effectiveness in pediatric patients have not been established.

The most common adverse reactions (greater than or equal to 5%) observed in clinical trials were headache, nausea, diarrhea, rash and phlebitis.

For more information visit http://www.DORIBAX.com.

Ortho-McNeil(TM) is committed to providing innovative, high-quality prescription medicines and resources for healthcare providers and their patients in hospitals and other care facilities. For more information, visit http://www.ortho-mcneil.com.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD), is part of Johnson & Johnson, the world's most broadly based producer of healthcare products. J&JPRD is headquartered in Raritan, NJ, and has facilities throughout Europe and the United States. J&JPRD is leveraging drug discovery and drug development in a variety of therapeutic areas to address unmet medical needs worldwide

Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock

2008-02-28T10:12:00.000-08:00

Background Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors.

Methods In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 µg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 µg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions.

Results A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P=1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P=0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P=0.76). A test for heterogeneity between these two study strata was not significant (P=0.10).

Conclusions Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors.

Discussion

In this multicenter, randomized, double-blind trial of low-dose vasopressin as compared with norepinephrine in patients with septic shock, we were not able to demonstrate any significant difference in the 28-day mortality rate (35.4% in the vasopressin group vs. 39.3% in the norepinephrine group, P=0.26). We were also unable to demonstrate any significant difference between the two study groups in 90-day mortality or the rate of organ dysfunction. There was no difference in the rates of serious adverse events between the vasopressin and norepinephrine groups. Infusions of low-dose vasopressin (0.03 U per minute) increased plasma vasopressin levels to approximately 70 to 100 pmol per liter from extremely low baseline vasopressin levels (median, 3.2 pmol per liter). Consistent with at least 14 previous trials in humans10,11,12,13,14,20,21,22,23,24,25,26,27,28 of low-dose vasopressin (≤0.1 U per minute), vasopressin infusion allowed a rapid decrease in the total norepinephrine dose while maintaining mean arterial pressure.10,11,12,29

Our study was prospectively powered to detect an absolute difference in mortality of 10% from an expected 60%. However, the observed mortality rates in both the vasopressin and norepinephrine groups were considerably lower than those in previous studies, perhaps because of overall improvements in the care of patients who have septic shock. Nonetheless, our data exclude with 95% confidence a harm associated with the use of vasopressin that was greater than 2.9% or a benefit that was greater than 10.7%.

The overall rates of serious adverse events were approximately 10% each in the vasopressin and norepinephrine groups. Previous studies raised the possibility that vasopressin infusion may increase the incidence of cardiac arrest.29 In contrast, we found that of 11 cardiac arrests reported in this study, 8 occurred in the norepinephrine group and 3 occurred in the vasopressin group. Our selection of a low dose of vasopressin (0.03 U per minute) and careful exclusion of patients who had acute coronary syndromes or severe heart failure could account for the lack of adverse cardiovascular effects of vasopressin infusion. If vasopressin becomes routine therapy and is given at higher doses or to patients with septic shock who have coexisting heart disease, the adverse reactions to vasopressin could be increased. Other reported adverse effects of vasopressin and norepinephrine include decreased cardiac output,11,14,29 mesenteric ischemia,21,30 hyponatremia (with vasopressin only), skin necrosis,31 and digital ischemia.32 More patients in the vasopressin group than in the norepinephrine group had digital ischemia; one patient in the vasopressin group required surgical intervention.

Our secondary hypothesis was that the beneficial effects of vasopressin as compared with norepinephrine would be more pronounced in the subgroup of patients with more severe septic shock. No significant interaction between treatment group and shock-severity subgroup (as defined a priori) was shown. Some of the analyses we performed suggested that vasopressin may be more beneficial in patients with less severe septic shock. However, the statistical significance of these observations is uncertain, especially because of the many statistical tests performed, and this finding should be considered only as a hypothesis-generating concept to be tested in future trials.33

Several limitations of our trial should be mentioned. The vasopressin was infused over a set range of doses, and we did not measure vasopressin levels as a guide to the dose or the duration of infusion. In addition, in this trial the mean arterial pressure at baseline was 72 to 73 mm Hg, essentially making this a study of the effects of low-dose vasopressin as a "catecholamine-sparing drug," not an evaluation of vasopressin in patients with catecholamine-unresponsive refractory shock. The mean time from meeting the criteria for study entry to infusion of the study drug (12 hours) was greater than the period that Rivers and colleagues4 identified as being important in early goal-directed therapy (6 hours), which may be one reason that we did not find a benefit of vasopressin as compared with norepinephrine.

In summary, we evaluated the effect of low-dose vasopressin (0.03 U per minute) when used in conjunction with catecholamine vasopressors in patients with septic shock. We did not find a significant reduction in mortality rates with vasopressin.

Supported by a grant (MCT 44152) from the Canadian Institutes of Health Research.

Drs. Russell, Walley, and Gordon report serving as officers and holding stock in Sirius Genomics, which has submitted a patent, owned by the University of British Columbia and licensed to Sirius Genomics, that is related to the genetics of vasopressin. The University of British Columbia has also submitted a patent related to the use of vasopressin in septic shock. Drs. Russell, Walley, and Gordon report being inventors on this patent. Drs. Russell and Walley report receiving consulting fees from Ferring, which manufactures vasopressin. Dr. Russell reports receiving grant support from Sirius Genomics, Novartis, and Eli Lilly; and Dr. Wally, from Sirius Genomics. No other potential conflict of interest relevant to this article was reported.

* Investigators who participated in the Vasopressin and Septic Shock Trial (VASST) are listed in the Appendix.

Source Information

From the iCAPTURE Centre, Vancouver, BC (J.A.R., K.R.W., A.C.G., M.M.S.); St. Paul's Hospital, Vancouver, BC (J.A.R., K.R.W., J.S., A.C.G., M.M.S., D.A.); Ottawa Hospital, University of Ottawa, Ottawa (P.C.H.); Kelowna General Hospital, Kelowna, BC, and University of British Columbia, Vancouver (C.L.H.); Mount Sinai Hospital, Toronto (S.M.); Toronto General Hospital, Toronto Western Hospital, and University of Toronto, Toronto (J.T.G.); and St. Joseph's Hospital and McMaster University, Hamilton, ON (D.J. Cook) — all in Canada; and Alfred Hospital and Monash University, Melbourne (D.J. Cooper); and Royal Melbourne Hospital and University of Melbourne (J.J.P.) — all in Melbourne, Australia.