Primary objective:* To determine the protective efficacy of repeated short term exposure to hookworm infection Secondary objectives:1. To explore the immunological response after repeated hookworm infections2. To evaluate the safety of and number of…
ID
Source
Brief title
Condition
- Helminthic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints
* Comparison of average egg counts of week 12 to 16 in the challenge phase by
Kato Katz between intervention group and placebo group
Secondary outcome
Secondary endpoints
* Adverse events collected during immunization phase and after controlled human
hookworm infection.
* Humoral (antibody) and cellular immunological changes after immunization and
after controlled human hookworm infection.
Background summary
Hookworm infection affects over 450 million people worldwide. Chronic infection
leads to malnutrition and iron-deficiency anaemia, particularly in children and
women of child-bearing age. Unfortunately, mass drug administration, the
cornerstone of hookworm control programmes, has not yet succeeded in
eradicating hookworm infection due to high rates of re-infection.
Controlled human hookworm infection (CHHI) trials were initially developed as a
model for to assess the beneficial effects of hookworm infection on autoimmune
diseases. CHHI models are also being developed to assess vaccine efficacy.
Another advantage of the controlled human hookworm infection model is its
unique possibility to study immunologic responses in a highly controlled
setting, thereby adding valuable knowledge of the host immune responses to
infection. Little is known about the factors influencing host protection
against repeated infection. In natural infection the human host develops an
inadequate immune response to infection. This may be caused by the
down-regulatory effect of the Th2 response caused by the adult worms in the
intestine. In animal models, short-term infections and infections with
radiation-attenuated larvae that do not develop into adult worms have shown to
induce protection against subsequent challenge. A similar model in humans,
using short-term infections abrogated by treatment can add valuable knowledge
about the initial immune response against hookworm infection which may in turn
aid in developing new vaccines.
Study objective
Primary objective:
* To determine the protective efficacy of repeated short term exposure to
hookworm infection
Secondary objectives:
1. To explore the immunological response after repeated hookworm infections
2. To evaluate the safety of and number of events after short term hookworm
infections
Study design
This study is a double-blind, randomised placebo-controlled trial.
Intervention
Twenty-four volunteers are randomized in a 2:1 ration to the intervention group
or placebo-group.
Immunization phase: In the intervention group, volunteers will receive three
infections with 50 L3 larvae of Necator americanus at a 3-week interval.
Volunteers in the placebo group will receive a mock infection with water to
maintain blinding. Two weeks after each infection all volunteers will be
treated with albendazole.
Challenge phase: Five weeks after the last treatment, all volunteers will
undergo controlled human hookworm infection with 50 L3 larvae and will be
followed for 16 weeks. At week 16 all volunteers will be treated with
albendazole, except a subset of a maximum of four volunteers who will be asked
to remain as donor for future trials. After treatment volunteers are followed
to ensure treatment was effective.
Study burden and risks
Burden: Volunteers are required to visit the study centre for eight visits
during the immunization phase and for twenty visits during the challenge phase.
The number of follow-up visits is the same for all groups. The amount of blood
collected per volunteer will be a maximum of 500 mL per 16 weeks. Faecal
samples will be taken every two to four weeks during the immunisation phase and
weekly in the challenge phase. Physical examinations will be performed when
clinically indicated and subjects will be asked to complete a diary of adverse
events on a daily basis during the challenge phase. Volunteers may experience
itching at the infection site and can experience gastro-intestinal side effects
from two to four weeks after the challenge.
Risks: Volunteers will be exposed to larval inoculum two or five times
depending on group allocation. Risks related to infection include skin rash and
gastro-intestinal symptoms. Symptoms are reversible and can be treated if
necessary. In a previous trial one in eight volunteers suffered from severe
abdominal pain necessitating earlier treatment, four in eight volunteers did
not experience any or only mild adverse events. In natural infection the main
risks are iron-defiency anaemia and protein loss, however in CHHI with healthy
volunteers this is not expected. Volunteers are treated four times with
albendazole during the course of the trial. Possible side effects posing risk
to volunteers related to albendazole treatment are headache, dizziness,
reversible alopecia and elevated liver enzymes. Clearance of infection is
confirmed by faecal Kato-Katz and qPCR. Volunteers are followed and if
necessary re-treated until the infection is completely cleared. No long-term
risks are expected.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
1. Subject is aged * 18 and * 45 years and in good health.
2. Subject has adequate understanding of the procedures of the study and agrees to abide strictly thereby.
3. Subject is able to communicate well with the investigator and is available to attend all study visits.
4. Subject agrees to refrain from blood donation to Sanquin or for other purposes throughout the study period.
5. For female subjects: subject agrees to use adequate contraception and not to breastfeed for the duration of study.
6. Subject agrees to refrain from travel to a hookworm endemic area during the course of the trial.
7. Subject has signed informed consent.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded from participation in this study:
1. Any history, or evidence at screening, of clinically significant symptoms, physical signs or abnormal laboratory values suggestive of systemic conditions, such as cardiovascular, pulmonary, renal, hepatic, neurological, dermatological, endocrine, malignant, haematological, infectious, immune-deficient, psychiatric and other disorders, which could compromise the health of the volunteer during the study or interfere with the interpretation of the study results. These include, but are not limited to, any of the following:
* positive HIV, HBV or HCV screening tests;
* the use of immune modifying drugs within three months prior to study onset (inhaled and topical corticosteroids and oral anti-histamines exempted) or expected use of such during the study period;
* having one of the following laboratory abnormalities: ferritine <10ug/L, transferrine <2.04g/L or Hb <6.5 mmol/L for females or <7.5 mmol/L for males.
* history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years;
* any history of treatment for severe psychiatric disease by a psychiatrist in the past year;
* history of drug or alcohol abuse interfering with normal social function in the period of one year prior to study onset;
* inflammmatory bowel syndrome;
* regular constipation, resulting in bowel movements less than three times per week.
2. Known hypersensitivity to or contra-indications for use of albendazole, including co-medication known to interact with albendazole metabolism (e.g. carbamazepine, phenobarbital, phenytoin, cimetidine, theophylline, dexamethasone).
3. Known allergy to amphotericin B or gentamicin.
4. For female subjects: positive urine pregnancy test at screening.
5. Positive faecal qPCR for hookworm at screening, any known history of hookworm infection or treatment for hookworm infection.
6. Being an employee or student of the department of Parasitology of the LUMC.
7. Current or past scars, tattoos, or other disruptions of skin integrity at the intended site of larval application.
Design
Recruitment
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL66725.058.18 |
| Other | volgt |