Clinical Trials

Date: 2015-07-27

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The New English Journal of Medicine

Company: Sanofi Pasteur (France)

Product: tetravalent dengue vaccine candidate

Action mechanism:

Disease: dengue  fever

Therapeutic area: Infectious diseases

Country: Thailand, Indonesia, Malaysia, The Philippines, Vietnam and Brazil, Colombia, Honduras, Mexico, Puerto Rico

Trial details:

• The Phase III clinical study conducted in Asia is a randomized, observer-blind, placebo-controlled multicenter trial. A total of 10,275 children aged 2 to 14 years from dengue endemic areas of Indonesia, Malaysia, the Philippines, Thailand and Vietnam participated in the study from 2011-2013 and were randomized to either receive three injections of the dengue vaccine or a placebo (2 to 1 ratio) at 6-month intervals. The primary endpoint was measured by the number of symptomatic virologically-confirmed dengue cases caused by any serotype. The study will continue with a long term follow up of the population. (NCT01373281)
• The primary objective of the phase III study in Latin America and the Caribbean was to assess the efficacy of the Sanofi Pasteur dengue vaccine candidate after three vaccinations in preventing symptomatic virologically-confirmed dengue cases. It is the second of two large-scale randomized, observer-blind, placebo-controlled multicenter trials. A total of 20,875 children aged 9 to 16 years from dengue endemic areas of Brazil, Colombia, Mexico, Honduras and Puerto Rico participated in the study and were randomized to either receive three injections of the dengue vaccine or a placebo (2 to 1 ratio) at 0, 6, and 12 months. (NCT01374516)
• Over 40,000 volunteers are participating in the Sanofi Pasteur dengue vaccine clinical study program (Phase I, II and III). Sanofi Pasteurs dengue vaccine candidate is in Phase III clinical studies. The two, pivotal Phase III efficacy studies involve more than 31,000 volunteers from Asia (Indonesia, Malaysia, the Philippines, Thailand and Vietnam) and Latin America (Brazil, Columbia, Honduras, Mexico and Puerto Rico). The Phase III evaluations provide pivotal data on efficacy, safety, and immunogenicity of the vaccine candidate in a broad population and different epidemiological environments and assess the potential impact of the vaccine on the disease burden.

Latest news:

• • On July 27, 2015, Sanofi Pasteur, the vaccines division of Sanofi, announced that new data analyses published in the New England Journal of Medicine (NEJM) provide a comprehensive picture of the potential public health impact of vaccinating endemic populations from pre-adolescence to adulthood against dengue. Not only is this the largest population at risk of dengue globally, but individuals 9 years of age and older also represent a highly mobile group capable of spreading disease more broadly during outbreaks and also contributing substantially to the economic burden of dengue, for example in number of lost school and work days due to the disease. The NEJM article reported results from a new pooled efficacy analysis of individuals 9 years of age and older at vaccination from the two Phase III studies of Sanofi Pasteur's dengue vaccine. The new analysis documented that the vaccine protects two-thirds of these individuals (66%) against dengue, providing even greater protection against two clinically-relevant manifestations of dengue, namely severe dengue (93%) and prevention of hospitalizations due to dengue (80%) that account for the greatest human and economic burden of dengue in endemic countries. In addition, the dengue vaccine candidate protected volunteers 9 years of age and older who were previously exposed to dengue (82%), as well as those who were naïve to dengue (52.5%) prior to vaccination.
• The clinical development program for the vaccine candidate includes studies with four-year, long-term follow-up phases, in line with WHO guidelines for dengue vaccine development. Results from first 25 months of the two Phase III efficacy studies were published in 2014. Interim data from the third year of these studies and interim data from the third and fourth years of the Phase II extension study in Thailand published in the new NEJM article confirm the continuing reduction of hospitalized dengue in the vaccinated population 9 years of age and older (NCT00842530 and NCT01983553). The third-year interim data from the Asian Phase III study identified the need for further long-term surveillance in children under 9 years of age to assess the impact of the dengue vaccine candidate in these younger children.
• Dr. Maria Rosario Capeding from the Research Institute for Tropical Medicine in the Philippines, who is a lead author on the NEJM article, points out the potential public health benefit of having a first dengue vaccine available to protect individuals 9 years of age and older. "This large, at-risk population includes the most dynamic members of the community who have the potential to spread disease widely and also contribute most to dengue's heavy societal impact in terms of school absences and lost work productivity. Certainly, individuals 9 years of age and older represent a compelling target group for an immunization program against dengue aimed at significantly reducing overall disease burden." Based on the totality of the safety and efficacy data for its dengue vaccine candidate, Sanofi Pasteur has decided to recommend a targeted age indication for the vaccine of 9 years of age and older in endemic countries, where the combination of disease burden and the vaccine's proven impact profile in this age group point to the greatest potential for reduction of dengue disease burden in these countries.
• • On November 3, 2014,  Sanofi Pasteur  announced the publication of the detailed results of the final landmark phase III clinical efficacy study in Latin America in The New England Journal of Medicine. Overall efficacy against any symptomatic dengue disease was 60.8 percent in children and adolescents 9-16 years old who received three doses of the vaccine. Analyses show a 95.5 percent protection against severe dengue and an 80.3 percent reduction in the risk of hospitalization during the study. The results of this second phase III efficacy study confirm the high efficacy against severe dengue and the reduction in hospitalization observed during the 25-month active surveillance period of the first phase III efficacy study conducted in Asia , highlighting the consistency of the results across the world.
• Safety analyses (solicited reactions, unsolicited events and Serious Adverse Events SAEs) during the study showed similar reporting rates between the vaccine and control groups and are consistent with the favorable safety profile observed during the 25-month active surveillance period of the previous efficacy study conducted in Asia. The full data of the Latin American study are also presented at the American Society of Tropical Medicine and Hygiene (ASTMH) Annual Meeting, 2-6 November 2014.
• Sanofi Pasteur’s phase III efficacy clinical study program for its dengue vaccine candidate was conducted in over 31,000 participants across 10 endemic countries in Asia and Latin America. Sanofi Pasteur will file for registration of its vaccine candidate and, subject to regulatory approval, the world’s first dengue vaccine could be available in the second half of 2015. Sanofi Pasteur is already producing the vaccine in a newly dedicated production facility in Neuville-sur-Saône, France, which will be capable of providing timely supply of large quantities of vaccines to meet the global public health demand.
• • On September 3, 2014, Sanofi Pasteur announced that the final landmark phase III efficacy study of its dengue vaccine candidate in Latin America successfully achieved its primary clinical endpoint. Results showed an overall significant reduction of 60.8 percent* of dengue disease cases in children and adolescents 9-16 years old after a three-dose vaccination schedule. Importantly, efficacy was observed against each of the four dengue serotypes. (95 percent CIs overall efficacy [52.0 percent, 68.0 percent]; Efficacy per serotype (ST1 50.3%, ST2 42.3%, ST3 74.0%, ST4 77.7%); 95 percent CIs reduction of the risk of hospitalization [64.7 percent, 89.5 percent]. Additional observations of the results showed a clinically important reduction by 80.3 percent in the risk of hospitalization due to dengue during the study. The results also showed in the study population an efficacy against dengue haemorrhagic fever (DHF), the severe form of dengue, which is consistent with the results released from Sanofi’s phase III dengue study in Asia. Lastly, the results suggest better protection in case of prior exposure to dengue. Safety analyses (solicited reactions, unsolicited events and Serious Adverse Events SAEs) during the study showed similar reporting rates between the vaccine and control groups and are consistent with the favorable safety profile documented in previous studies (phase I, II, III).
• A full analysis of the efficacy and safety data from the phase III study will be completed and reviewed by external experts before publication in a peer-reviewed scientific journal and presentation at the American Society of Tropical Medicine and Hygiene (ASTMH) Annual Meeting, 2-6 November 2014, in New Orleans, Louisiana, US.
• • On July 11, 2014, Sanofi Pasteur announced the publication in The Lancet of the detailed results of its first landmark phase III dengue vaccine efficacy study conducted in five countries in Asia. Results show overall efficacy against symptomatic dengue of 56.5%* in children aged 2 to 14 years old after a three-dose vaccination schedule. Importantly, analyses show an 88·5%* reduction of dengue haemorrhagic fever, the severe form of dengue, according to the WHO criteria1. The study also showed a clinically important reduction in the risk of hospitalization due to dengue by 67%* during the study. The favorable vaccine safety profile observed during the 25 month follow up of the phase III study in Asia is consistent with the safety profile documented in other studies (phase I, II, IIb). Safety analyses (solicited reactions, unsolicited events and Serious Adverse Events SAEs) during the study showed similar reporting rates between the vaccine and control groups. SAEs were consistent with medical disorders in this age group and were mainly infections and injuries. Safety is continuously reviewed by an independent data monitoring committee. To date, 27,000 children, adolescents and adults have been vaccinated with three doses of the candidate dengue vaccine throughout the clinical studies. The four dengue virus serotypes have circulated during the study with a distribution representative of the epidemiology in Asia. The measured efficacy of the vaccine during the 25 months observation of the study is consistent across countries and appears to vary by dengue serotype (between 34.7% and 72.4%) and by age. The results of this first, large-scale efficacy study will be supplemented by results from a second, large-scale phase III study in Latin America and the Caribbean, including more than 20,000 children and adolescents aged 9 to 16 years old from Brazil, Colombia, Honduras, Mexico and Puerto Rico. * 56.5% (95% CI: 43.8-66.4); 88·5% (95% CI 58·2 to 97·9); 67.2% (95% CI: 50.3 to 78.6).
• • On April 28, 2014, Sanofi Pasteur has announced that the first of two pivotal Phase III efficacy studies with its dengue vaccine candidate has achieved its primary clinical endpoint. The efficacy study showed a significant reduction of 56% of dengue disease cases. Initial safety data are consistent with the good safety profile observed in previous studies. Full analysis of the data will be undertaken in the coming weeks and reviewed by external experts prior to disclosure at an upcoming international scientific congress and publication in a peer-reviewed journal later this year. The results of this first, large-scale efficacy study will be further complemented by results in Q3 2014 from a second, large-scale study currently conducted in Latin America, including more than 20,000 volunteers from Brazil, Colombia, Honduras, Mexico and Puerto Rico.
• • On July 25, 2012, Sanofi Pasteur, the vaccines division of Sanofi, has announced that its tetravalent dengue vaccine candidate demonstrated proof of efficacy against dengue, a threat to almost 3 billion people, in the world’s first ever dengue efficacy trial conducted in Thailand, with excellent safety. The vaccine generated antibody response for all four dengue virus serotypes. Evidence of protection was demonstrated against three of the four virus serotypes circulating in Thailand. Analyses are ongoing to understand the lack of protection for the fourth serotype in the particular epidemiological context of Thailand. Importantly, the results confirm the excellent safety profile of the vaccine candidate. The full data resulting  from this first efficacy trial are currently under review by scientific and clinical experts, as well as public health officials. Detailed results of this study will be published in a peer-reviewed journal and presented to the scientific community later this year.
• Large scale phase III dengue vaccine clinical studies with 31,000 participants are underway in 10 countries of Asia and Latin America. These studies will generate important additional data in a broader population and in a variety of epidemiological settings to demonstrate vaccine efficacy against the four circulating dengue virus serotypes. Sanofi Pasteur’s investigational dengue vaccine - which targets all four virus types - has been evaluated in clinical studies (Phase I, II) in adults and children in the U.S., Asia and Latin America. Overall, an immune response against all four serotypes was observed after three doses of the vaccine. The vaccine is well tolerated with a similar safety profile after each dose.

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