Clinical trial NCT02942485
Conditions: GIARDIASIS
Sponsor: Helsinki University Central Hospital
Start date: 2016-12-01; Completion date: 2019-12-31
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study investigates the efficacy and safety of rectally administered metronidazole for pediatric Giardia lamblia infection, as well as the acceptance of this treatment regimen by patients/caregivers. The investigators hypothesize that rectal metronidazole is non-inferior to single-dose of oral tinidazole and will cure at least 72% of patients, a well as will be tolerated as good as tinidazole.

Detailed description:
Approximately 180 children (age 6 months to 10 years) whose clinical symptoms could be explained by giardiasis and whose fecal samples will test positive for the presence of G.lamblia in Uusimaa laboratory (HUSLAB) will be recruited.

The study will be performed as an open-label trial. Patients will be randomized during primary visits alternately into two groups by random allocation to receive either of the two study drugs.

Patients from group 1 will be treated with a standard regimen of oral tinidazole (Fasigyn) at a single dose of 50 mg/kg, maximum 2 g/dose. Patients from group 2 will be given rectal metronidazole (Flagyl) 500 mg/dose for children weighing 10-14,9 kg, 1000 mg/dose for those weighing 15-29,9 kg and 1500 mg/dose for those weighing 30-44,9 kg. Suppositories will not be halved. Patients will be given 1 dose/day for 3 days. The first dose of metronidazole will be administered during the primary clinical visit and 2 additional doses will be provided to the parents for home administration.

Fecal samples will be collected from the study patients on day 7-10 post-treatment and will be analyzed in HUSLAB for the presence of G.lamblia antigen by enzyme immunoassay (EIA). Early collection of samples on day 7-10 will help to avoid the risk of tests being positive due to reinfection.

If any of the patients will not clear the infection by day 10, he/she will be invited to a second visit and re-treated. Patients from group 1 will be re-treated by rectal metronidazole and patients from group 2 by oral tinidazole, thus performing a cross-over. Follow-up stool samples will be collected.

Criteria for clinical cure will be resolution of symptoms by day 10 and microbiological cure will be defined as negative G.lamblia antigen test from fecal samples collected on day 7-10 post-treatment.

Arms: arm 1: Patients will be given rectal metronidazole (Flagyl) 500 mg/dose for children weighing 10-14,9 kg, 1000 mg/dose for those weighing 15-29,9 kg and 1500 mg/dose for those weighing 30-44,9 kg. Suppositories will not be halved. Patients will be given 1 dose/day for 3 days. arm 2: Patients will be treated with a standard regimen of oral tinidazole (Fasigyn) at a single dose of 50 mg/kg, maximum 2 g/dose
Interventions: intervention 1: Metronidazole intervention 2: Tinidazole
Intervention descriptions: intervention 1: P/r suppositories intervention 2: P/o tablets

Protocol documents:
Prot_000.pdf: 
Research protocol version 2 / 1.9.2016 
Code: PGLIT2016 
 
Treatment of Giardia lamblia infections in children: randomized 
open-labeled trial comparing rectal metronidazole with oral tinidazole 
 
 
 
 
1. BACKGROUND 
 
Epidemiology and clinical significance of Giardia lamblia infections 
Giardia lamblia (G.lamblia) is a protozoan which infects small intestine of humans and other 
mammals. Ingestion of food or water contaminated with cysts represents the common route of 
transmission. The incubation period lasts from 7 to 28 days. In Nordic countries, including Finland, 
prevalence of giardiasis is 5.81 % in symptomatic population (Hörman, 2004). Infected persons can 
remain asymptomatic or present with a variety of symptoms, ranging from self-limited acute 
diarrhea to a chronic disease with abdominal pain, diarrhea, and failure to thrive. 
 
Diagnostic tests 
Giardiasis is commonly diagnosed by analyzing fecal samples and detecting G.lamblia cysts on 
microscopy. However, this method requires repeated stool samples to detect intermittent shedding 
of G.lamblia, e.g. when assessing the response to treatment. Whereas a single positive stool enzyme 
immunoassay (EIA) for G.lamblia antigen provides a sensitivity close to 100% and specificity of 
>90% for diagnosis of giardiasis (Jahan, 2014). 
 
Treatment regimens 
Nitroimidazoles (metronidazole, tinidazole and others) represent drugs of choice for giardiasis. 
Tinidazole given orally at a single dose of 50 mg/kg cures 72-100% of the patients (Escobedo, 
2007). Trials examining oral metronidazole implicate different regimens of single and multiple 
daily doses for 1 to 10 days, resulting in variable cure rates. Metronidazole efficacy improves when 
prolonged (>1 day) treatment courses are administered, compared to single-dose therapy. 
Rectal tinidazole preparation has been used for years in giardiasis treatment in Finland resulting in a 
satisfactory response rate, until the drug became unavailable. This treatment option has been 
particularly useful in children unable to tolerate oral tinidazole due to its unpleasant taste. 
Rectally administered metronidazole reaches therapeutical concentrations in plasma and has been 
highly effective in treatmen of e.g. vaginal trichomoniasis (Panja, 1982). Rectal administration of 
metronidazol results in lower serum concentrations, necessitating higher dosage (Lau, 1992). 
Side effects of nitroimidazoles are usually mild and self-limited. They include abdominal pain, 
nausea, diarrhea, metallic/bitter taste, headache and dizziness. 
 
 
2. RATIONALE FOR THE PRESENT STUDY 
 
While oral nitroimidazoles are the drugs of choice for lambliosis, the efficacy and safety of rectally 
delivered preparations remains unknown. Oral administration of nitroimidazoles in children often 
proves difficult due to the absence of palatable pediatric formulations. Some children refuse to 
swallow the medicine or vomit it out. Parents often fail to give oral tinidazole at home, which 
necessitates controlled drug administration in the hospital, and sometimes even nasogastrial tube 
placement. Thus, a rectally administered drug may represent a solution for the treatment of children 
who are unable to take oral preparations. 


 
 
3. AIMS 
 
This study investigates the efficacy and safety of rectally administered metronidazole, as well as the 
acceptance of this treatment regimen by patients/caregivers. We hypothesize that rectal 
metronidazole is non-inferior to single-dose of oral tinidazole and will cure at least 72% of patients. 
We also hypothesize that rectal metronidazole will be tolerated as good as tinidazole. This study 
will provide significant data on the new option for treatment of giardiasis. The results will be 
published as a single article in an international journal in the field of pediatrics/parasitology. 
 
 
4. PATIENTS 
 
We will recruit approximately 180 children (age 6 months to 10 years) whose clinical symptoms 
could be explained by giardiasis and whose fecal samples will test positive for the presence of 
G.lamblia in Uusimaa laboratory (HUSLAB). Exclusion criteria will be: 1) age <6 mo or >10 years, 
2) weight <9.5 kg, 3) the absence of symptoms, 4) co-infection with another pathogen, which may 
cause giardiasis-like symptoms. 
 
 
5. METHODS 
 
1) The Epidemiologic operations unit of the City of Helsinki will issue information about our study 
to all its health stations. This note will contain information about the possibility to refer a child with 
diagnosed G.lamblia infection for ambulatory treatment to Children’s Hospital, Helsinki University 
Central Hospital. Researchers will contact the referred patients/caregivers and invite them to 
participate in the study. If the family refuses the participation, this will not affect the availability and 
quality of treatment and standard care will be provided to the patient referred. 
 
2) In case the primary diagnosis of G.lamblia infection is done by finding a positive G.lamblia 
antigen from fecal samples, we will perform additional microscopy examination of stool specimens 
to exclude other possible parasites/protozoa as a cause of patients symptoms. 
 
3) Clinical data on the patient's symptoms will be collected during interviews at the clinical visits 
and by phone interviews after treatment. A structured questionnaire will assess clinical treatment 
response, acceptance and possible side effects. 
 
4) The study will be performed as an open-label trial. We will randomize patients during primary 
visits alternately into two groups by random allocation to receive either of the two study drugs.  
 
5) Patients from group 1 will be treated with a standard regimen of oral tinidazole (Fasigyn) at a 
single dose of 50 mg/kg, maximum 2 g/dose. Patients from group 2 will be given rectal 
metronidazole (Flagyl) 500 mg/dose for children weighing 10–14,9 kg, 1000 mg/dose for those 
weighing 15–29,9 kg and 1500 mg/dose for those weighing 30–44,9 kg. Suppositories will not be 
halved. Patients will be given 1 dose/day for 3 days. The first dose of metronidazole will be 
administered during the primary clinical visit and 2 additional doses will be provided to the parents 
for home administration. 
 
6) Fecal samples will be collected from the study patients on day 7-10 post-treatment and will be 
analyzed in HUSLAB for the presence of G.lamblia antigen by EIA. Early collection of samples on 
day 7-10 will help to avoid the risk of tests being positive due to reinfection. 


 
7) If any of the patients will not clear the infection by day 10, he/she will be invited to a second visit 
and re-treated. We will re-treat patients from group 1 by rectal metronidazole and patients from 
group 2 by oral tinidazole, thus performing a cross-over. Follow-up stool samples will be collected. 
 
8) If the patient remains infected after two courses of treatment, mepacrine hydrochloride will be 
administered according to the clinical routine for imidazole-resistant G.lamblia infections. 
 
9) Criteria for clinical cure will be resolution of symptoms by day 10 and microbiological cure will 
be defined as negative G.lamblia antigen test from fecal samples collected on day 7-10 post-
treatment. 
 
10) Clinical and microbiological data will be coded and analyzed using IBM SPSS Statistics 
software.  
 
 
6. ETHICAL ASPECTS 
 
The study will provide valuable information on the treatment of giardiasis. All of the study patients 
will be given treatment for G.lamblia infection and to those patients who will not respond to the 
regimen under evaluation a standard course of therapy will be given. 
We will apply for the permissions to carry out the study from the Ethic's Board and Finnish 
Medicines Agency.  
Informed consent will be obtained from the patients/caregivers, as well as from children aged ≥7 
years.  
Clinical and laboratory data will be collected into an electronic database. All the participants will be 
given codes and personal data will not be recorded. Only researchers listed on page 1 of this 
protocol will have access to the database. 
 
 
 
 
7. RESEARCHERS 
 
Eeva Salo, MD, PhD, associate professor, is a pediatrician and pediatric infectious disease 
specialist. She has a staff position at Hospital for Children and Adolescents, Helsinki University 
Hospital. She will be responsible for planning and organization of the study. 
 
Svetlana Kostjukovits, MD, is a pediatrician and PhD student at the University of Helsinki. She will 
be responsible for recruiting the patients, carrying out clinical visits and collecting research data. 
 
Tarja Saavalainen-Hakala is a nurse working in the Pediatric Infectious Diseases ambulatory 
services at the Hospital for Children and Adolescents, Helsinki University Hospital. She will be 
helping with patients recruitment and their clinical visits. 
 
Susanna Bjorkbacka is a nurse working in the Pediatric Infectious Diseases ambulatory services at 
the Hospital for Children and Adolescents, Helsinki University Hospital. She will be helping with 
patients recruitment and their clinical visits together with Tarja Saavalainen-Hakala. 
 
 
8. FUNDING 
 


The primary diagnostic tests and follow-up fecal samples belong to the established clinical routine 
and are a part of standard management of patients with giardiasis. Drugs for the study will be 
covered by the Hospital for Children and Adolescents, Helsinki University Hospital as a part of 
routine patients care. 
 
 
9. REFERENCES 
 
Escobedo AA, Cimerman S. Giardiasis: a pharmacotherapy review. Expert Opin Pharmacother. 
2007 Aug;8(12):1885-902. Review. 
 
Hörman A, Korpela H, Sutinen J, Wedel H, Hänninen ML. Meta-analysis in assessment of the 
prevalence and annual incidence of Giardia spp. and Cryptosporidium spp. infections in humans in 
the Nordic countries. Int J Parasitol. 2004 Nov;34(12):1337-46. 
 
Jahan N, Khatoon R, Ahmad S. A Comparison of Microscopy and Enzyme Linked Immunosorbent 
Assay for Diagnosis of Giardia lamblia in Human Faecal Specimens. J Clin Diagn Res. 2014 
Nov;8(11):DC04-6. Epub 2014 Nov 20. 
 
Lau AH, Lam NP, Piscitelli SC, Wilkes L, Danziger LH. Clinical pharmacokinetics of 
metronidazole and other nitroimidazole anti-infectives. Clinical Pharmacokinetics 1992;23(5):328-
64. 
 
Panja SK. Treatment of trichomoniasis with metronidazole rectal suppositories. Br J Vener Dis. 
1982 Aug;58(4):257-8.