Phase I-II study of live oral cholera vaccine 638 in healthy adult volunteers in Cuba.

General information

Section to complete general information about the trial: scientific and public title, protocol identifiers, sponsors and Source(s) of Monetary or Material Support.

Scientific title:

Randomized, double-blind, controlled, phase I-II study to determine the safety, reactogenicity and immunogenicity of a single dose of 1-9 x 10E9 CFU of the live attenuated oral cholera lyophilized vaccine obtained from 638 Vibrio cholerae O1 El Tor Ogawa strain, administered by oral route in healthy adult volunteers from both sex.

Secondary indentifying numbers:

CHO0104

Issuing authority of the secondary identifying numbers:

Finlay Institute

Source(s) of monetary or material support:

Council of State of the Republic of Cuba

Authorization for beginning

Section to complete information about the regulatory approval of clinical trial: regulatory agency name, approval date and reference number in the agency.

Regulatory instance to authorize the initiation of the study:

Center for State Control of the Quality of Drugs(CECMED)

Authorization date :

24/12/2004

Reference number:

095/05.031.04B

Principal investigator

Section to complete information about Email address, telephone number and postal address of the Principal Investigator.

First name:

Manuel

Last name:

Diaz Jidy

Medical Specialty :

Specialist of Second Degree in Internal Medicine

Affiliation:

"Pedro Kouri" Institute of Tropical Medicine

Postal address:

Autopista Novia del Mediodía 6 1/2 entre Autopista Nacional y Carretera Central, Post Office Box 601

City:

Havana

País:

Cuba

Zip Code:

11400

Telephone:

+53-72020430

Email address:

email@not.entered [1]

Clinical sites to participate

Section to complete the data related to the clinical sites involved in the trial: site and responsible investigator for every site.

Countries of recruitment:

Cuba

Clinical sites:

Not applicable

Research ethics committees:

“Pedro Kouri” Institute of Tropical Medicine. October 4, 2004.

Recruitment status

Section to complete information about the recruitment status and the date of first enrolment subject

Recruitment status:

Complete

Date of first enrollment:

21/02/2005

Health condition and Intervention

Section to complete information about the primary medical condition(s) or problem(s) studied and, a characteristics of the intervention(s).

Health condition(s) or Problem(s) studied:

Cholera disease

Health condition(s) code:

Cholera/ prevention & control

Healthy Volunteers

Vibrio Infections

Gram-Negative Bacterial Infections

Bacterial Infections

Waterborne Diseases

Environmental Illness

Intervention(s):

The vaccine under study, formulated at the Finlay Institute, is a lyophilized live oral vaccine, composed by the attenuated strain 638 V. cholerae from the serogroup O1, the biotype El Tor and the serotype Ogawa, as the pharmaceutical active ingredient and lyoprotectors: skimm milk, peptone and sorbitol. The 638 strain obtained at the CNIC does not have CT genes and others also present into the CTXphi phage, and it has the haemaglutinin protease gene (hap) inactivated, in which the endoglucanase A (celA) of the Clostridium thermocellum is inserted. The vaccine is orally feeding in a single dose. The placebo group will be fed with lyoprotectors without the pharmaceutical active ingredient (the attenuated 638 strain). This trial was designed in two stages; stage 1 evaluated two antiacid as the vaccine dissolvents. In this stage participated 16 volunteers whom were feeding with the vaccine, 8 volunteers with the vaccine diluted into the antiacid A (1,33% sodium bicarbonate ), and the 8 remain volunteers with the vaccine diluted into the antiacid B (sodium bicarbonate, ascorbic acid, manitol, lactose, sodium saccharine, polivinilpirrolidone). In the stage 1 participated 8 volunteers from the placebo group whom were feeding with lyoprotectors diluted into the antiacids; 4 with the antiacid A and 4 with the antacid B. The stage 2 was conformed by 18 volunteers whom were fed with the vaccine dissolved into the antiacid B and 6 volunteers from the placebo group whom were fed with lyoprotectors diluted into the antiacid B.

Intervention code:

Cholera Vaccines

Vaccines, Attenuated

Vibrio cholerae O1

Administration, Oral

Placebos

Outcomes and Timepoint

Section to complete information about primary and secondary outcomes including. It includes the metric or method of measurement used and, the time point for every outcome.

Primary outcome(s):

Primary objectives: 1-To assess safety of 1-9x10E9 CFU of a single dose of 638 V. chorelae O1 El Tor Ogawa, a lyophilized live attenuated oral cholera vaccine. 2-To assess reactogenicity during 5 days after application of vaccine or placebo. 3-To assess the vibriocidal antibody response against Ogawa serotype on days 14, 28, 42, at month 6 and one year after. Primary endpoints: Safety and Reactogenicity: 1-Incidence of any expected grade 3 adverse event within 5 days after vaccine and (or) placebo administration. 2-Incidence of any other expected adverse events taking place within 7 days after treatment. 3-Incidence, intensity and relationship to the vaccine and (or) placebo administration of any unexpected adverse even during the whole trial (30 days). 4-Incidence and relationship to the vaccine and (or) placebo administration of any serious adverse events during the whole trial (30 days). 5-Incidence of clinical lab tests with pathologic values 7 days after vaccine and (or) placebo administration. 6-Identification of attenuated 638 strain V. cholerae O1 El Tor Ogawa, excreted by volunteers 5 days before and 3 days after the antibiotic treatment. Immunogenicity: 1-The Geometrical Mean Titer (GMT) of vibriocidal antibodies: Estimation of the mean of vibriocidal antibody titers detected in serum samples on days 14, 28, 42, at month 6 and one year after treatment in comparison with the titers before vaccine and (or) placebo administration. 2-Assessment of seroconversion: Seroconversion defined as a fourfold increase of vibriocidal antibody titers on days 14, 28, 42, at month 6 and one year after treatment in comparison with the titers before vaccine and (or) placebo administration.

Key secondary outcomes:

Secondary objective: To demonstrate vaccine plus antiacid proposed as a final formulation, is suitable as the vaccine mixed with 1.33% sodium bicarbonate. Secondary endpoints: 1-Incidence, intensity and relation to the placebo plus antiacid A administration of any unexpected adverse event during the first stage (30 days). 2-Incidence, intensity and relation to the placebo plus B antiacid administration of any unexpected adverse event during the first stage (30 days). 3-Statistic signification (“p value”) between immunogenicity results of volunteers who were fed with placebo mixed with antiacid A and immunogenicity results of volunteers fed with placebo mixed with antiacid B.

Selection criterias

Section to complete information about the inclusion and exclusion criteria for participant selection, including age and gender.

Gender:

Male/Female

Minimum age:

18 years

Maximum age:

40 years

Inclusion criteria:

1-Healthy female or male aged 18 to 40 years 2-Free from obvious health problems as established by medical history, clinical examination, laboratory tests and psychometric tests before entering into the study. 3-Written informed consent obtained from the subjects. 4-To approve a written examination in order to ensure the volunteers understanding related to the study (trial) and others elemental knowledge about cholera.

Exclusion criteria:

1-Previous history of immunodeficiency. 2-Cardiovascular, respiratory, renal, hematological, hepatic, gastrointestinal, neurological, endocrine, and psychiatric diseases or reticuloendothelial system disorders detected during the clinical examination or by laboratory tests. 3-History of Allergy to tetracyclines. 4-Previous history of immunization with cholera vaccine or infection with cholera. 5-Administration of immunoglobulins and/or antibiotics within 30 days preceding the treatment. 6-Positive serological test for human HIV-1-2 virus antibody. 7-Positive serological test for human hepatitis B surface antigen, or hepatitis A and C antibodies. 8-Stool cultures positive for an enteric pathogen. 9-Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs prior to the treatment. Inhaled and topical steroids are allowed. 10-Administration of a vaccine not foreseen by the study protocol during the period starting one month before the application of the study vaccine and ending one month after that application. 11-Acute disease at the time of enrollment. Acute disease is defined as the presence of a moderate or severe illness with or without fever. 12-Do not approve a written examination in order to ensure the volunteers understanding related to the study (trial) and others elemental knowledge about cholera. 13-Pregnancy adverted by women or detected by mean of a rapid B-HCG pregnancy test on urine. Women during the proximity of the menstrual period at the very moment of the admission of the trial were discarded.

Type of population:

Adults

Type of participant:

Healthy volunteers

Study design

Section to complete information about the characteristics of the study design.

Type study:

Interventional

Purpose:

Treatment

Allocation:

Randomized controlled trial

Masking:

Double Blind

Control group:

Placebo

Study design:

Parallel

Phase:

1-2

Target sample size:

Contact for public queries

Section to complete information about Email address, telephone number and postal address of the contact who will respond to general queries, including information about current recruitment status

First Name:

Hilda

Middle Name:

Maria

Last Name:

Garcia Sanchez

Specialty:

Bachelor in Biochemistry

Affiliation:

Finlay Institute

Postal Address:

Casa F. Ave 27, No 19805, La Lisa.

City:

Havana City

País:

Cuba

Zip Code:

11600

Telephone:

72731218

Email :

hgarcia@finlay.edu.cu [2]

Contact for scientific queries

Section to complete information about Email address, telephone number and postal address of the contact who will respond to scientific queries.

First Name:

Rodrigo

Last Name:

Valera Fernández

Specialty:

II Specialist in Microbiology

Affiliation:

Finlay Institute

Postal Address:

Casa F. Ave 27, No 19805, La Lisa.

City:

Havana

País:

Cuba

Zip Code:

11600

Telephone:

72731218

Email :

rvalera@finlay.edu.cu [3]

Registration and Update

Section to complete information about the name of Primary Registry, date of registration and the unique ID number assigned by the registry (RPCEC).

Primary registry:

RPCEC

Unique ID number:

RPCEC00000053

Date of Registration in Primary Registry:

2008-09-19

Record Verification Date:

2008-09-15 20:00

Link to the spanish version:

Click here [4]