Primary objectives: • To establish two hookworm-infected donors to set up the controlled human hookworm infection model in Gabon • To study early-phase immune responses to hookworm exposure during the first four weeks after challengeExploratory…
ID
Source
Brief title
Condition
- Helminthic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Detection of hookworm eggs by faeces microscopy (Kato-Katz) at week 12 and 13
post-infection.
• Humoral and cellular immunological changes in the first month after exposure
to hookworm
Secondary outcome
• Number of adverse events following exposure to hookworm larvae
Background summary
A safe and efficacious vaccine against hookworm is urgently needed. Animal
models to test vaccines are not available, therefore controlled human hookworm
infection (CHHI) studies can be of great value to speed up vaccine development.
Because immune responses of hookworm-endemic populations clearly differs from
naïve populations, we have recently embarked on a project to transfer the
hookworm controlled human infection model to our research collaborators at
CERMEL. In order to train and certify staff at CERMEL in Gabon, we will need
continued access to hookworm eggs and larvae. Once training has been completed,
the Gabonese team will establish chronic donors with a (local) Gabonese
hookworm strain. Should there be technical difficulties with establishing
chronic donors and obtaining infectious larvae, the hookworm donors in Leiden
will serve as a backup to provide infectious larvae. Moreover, we will use this
study to further elucidate early phase immune responses to hookworm
exposure.
The aim of this study therefore is to recruit healthy individuals to become
hookworm donors for future CHHI studies at the LUMC and Gabon and to study
early-phase immune responses.
Study objective
Primary objectives:
• To establish two hookworm-infected donors to set up the controlled human
hookworm infection model in Gabon
• To study early-phase immune responses to hookworm exposure during the first
four weeks after challenge
Exploratory objective:
• To describe the number of adverse events following single exposure to
hookworm larvae
Study design
An open-label intervention study
Intervention
Four participants will be exposed to 50 Necator americanus (Na) larvae at week
0. Weekly follow up site visits will take place until week 4 after infection.
Afterwards weekly follow up phone calls, will take place to collect adverse
events until 13 weeks after the first infection. At week 12 and 13,
participants will provide a total of four stool samples for egg quantification.
Based on these results, two participants will be treated at week 14, while the
other two will remain infected and become donors for the rest of the study.
Those treated early will come to evaluate treatment at week 15 and week 17.
After week 14 donors will regularly (roughly 5-10 times/year) be asked to
donate faeces (= on demand donation). After 2 years, or if volunteers decide to
withdraw earlier, treatment with albendazole will be initiated. Treatment of
donors will be evaluated at 1 and 3 weeks after dosing.
Study burden and risks
Benefits: There is no benefit of participation in the trial for the individual
volunteers. Therefore the risk and discomfort of participation for individual
volunteers should be carefully weighed against the scientific advantage of the
controlled human Na infection model, in particular for vaccine and drug
development.
Burden and risks: The number of study visits varies between participants. The
two volunteers that become chronic donors visit the trial centre at least 12
times, excluding on demand donations. Those that are treated early visit the
centre 11 times. Check-up visits last approximately 15 minutes. The controlled
human hookworm infection visits last two hours. During check-up visits blood is
drawn. Volunteers are required to regularly collect faeces samples.
In natural infection the main risks of hookworm infection are iron-deficiency
anaemia (IDF) and protein losses. This, however, has not been observed in
healthy volunteers in previous controlled human hookworm trials. The risks to
volunteers pertain to exposure to larval inoculum and treatment with
albendazole. Adverse events expected after infection include skin reactions
(rash and itching) and gastro-intestinal symptoms, such as diarrhea and
abdominal pain. Skin rash may occur immediately after infection. The duration
of the rash in volunteers exposed to 1x 50 larvae ranges between 0 and 34 days
(median: 27 days). Itching can also occur from the moment of infection and
typically lasts for three days (median duration), with a maximum of 23 days.
Volunteers with a darker skin may experience depigmentation or
hyperpigmentation at the site of larval inoculation. This may result in
permanently visible lesions of approximately one millimetre. Our experience in
previous CHHI infections is that nearly all volunteers develop
gastro-intestinal adverse events, but that there is great interindividual
variation in the severity of these gastro-intestinal adverse events.
Previously, we did not find a relationship between infectious dose and
gastrointestinal events. Treatment with albendazole has shown to effectively
resolve the symptoms in the previous trials. Side effects of albendazole may
include headache, dizziness, transient alopecia and elevated liver enzymes.
Liver enzymes will be checked after albendazole treatment. In longer
administration of albendazole neutropenia has been described, however this is
unlikely due to the short course given in this trial (3 days). Volunteers in
the study will be exposed to risks associated with chronic hookworm infection
that include iron deficiency, iron-deficiency anaemia, and chronic
gastrointestinal symptoms, (i.e. flatulence, abdominal pain, diarrhea, nausea,
vomiting, abdominal bloating). Previously, we found that our chronic donors
(n=7) are asymptomatic after 16 weeks and do not develop anaemia. Donors also
visit the trial centre one year after infection for follow-up.
Group-relatedness: Not applicable
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
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 is male.
3. Subject has adequate understanding of the procedures of the study and agrees
to abide strictly thereby.
4. Subject is able to communicate well with the investigator and is available
to attend all study visits.
5. Subject agrees to refrain from blood donation to Sanquin or for other
purposes throughout the study period.
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 <7.5 mmol/L;
• 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;
• inflammatory 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. Positive faecal qPCR for hookworm at screening, any known history of
hookworm infection or treatment for hookworm infection.
5. Being an employee or student of the department of Parasitology of the LUMC.
6. Current or past scars, tattoos, or other disruptions of skin integrity at
the intended site of larval application.
Design
Recruitment
metc-ldd@lumc.nl
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 | NL75220.058.20 |
| Other | NL9178 |