GiardiaTREAT & GiardiaREF

GiardiaTREAT & GiardiaREF:   study concept overview

GiardiaTREAT: Observational multi-centre study on the tolerability & clinical efficacy of 1st-line Giardia lamblia treatment regimens

Background:
Giardia lamblia (syn. G. duodenalis, G. intestinalis) is a flagellated protozoan that parasitizes the upper part of the small intestine of mammals, including humans, pets and livestock. Transmission occurs via the faecal-oral route by ingestion of cysts, the infective stage of the parasite, either by direct person-to-person transmission or indirectly through contaminated water and food. The clinical picture ranges from asymptomatic shedding of giardia cysts to symptomatic presentations with abdominal complaints, nausea, vomiting and acute or chronic diarrhoea. G. lamblia is considered the most common parasite causing diarrheal disease worldwide. Recently, giardiasis has been included in the ‘Neglected Disease Initiative’, estimating that 280 million people are infected worldwide with G. lamblia each year. In a systematic review on traveller diarrhoea, G. lamblia was found in 1.5 to 6.5% of all episodes, depending on the continent of exposure. Among 7442 travellers consulting travel clinics for diarrheal complaints after a stay in tropical and subtropical regions, G. lamblia was found in about 10% of all episodes and was the most frequently identified causative pathogen. Although the link between G. lamblia and acute diarrhoea is still debated in children living in endemic settings, the association has been well established  for persistent (> 14 days) diarrhoea in children living in endemic settings as well as for acute and persistent diarrhoea in (adult) travellers.
Among the 1st-line treatment options metronidazole and other 5-nitroimidazole derivatives are the most frequently used drugs. Concerning the question of how to treat giardiasis with these drugs, a multiplicity of studies comparing different drug- and dosage-regimens and as many expert opinions exist. An actual survey conducted among the TropNet member sites confirms the diversity of 1st- (as well as 2nd-line) treatment regimens currently used throughout Europe.

Various studies have shown that the median efficacy of the 5-nitroimidazole based 1st-line treatment regimens (e.g. metronidazole, tinidazole, ornidazole) is similar, achieving about 90% of clinical AND parasitological cure. However, most randomized controlled trials comparing the classic treatment (metronidazole for 5-10 days) with single dose regimens of other 5-nitroimidazole drugs (tinidazole or ornidazole) were small and of poor quality. In addition, little data exist on the tolerability of the different drug regimens, which would be important to choose the regimen with the lowest rate of side-effects. Therefore, we initiated this observational study focusing on the tolerability of selected 5-nitroimidazole based 1st-line treatment regimens for G. lamblia.

Objectives
Main objective:
To evaluate the tolerability of 5-nitroimidazole based 1st-line G. lamblia treatment regimens
Additional objectives:
1. To assess the rate of treatment adherence and the rate of side-effect related treatment cessation of different 5-nitroimidazole based 1st-line treatment regimens
2. To assess the overall clinical efficacy of 5-nitroimidazole based 1st-line treatment regimens
3. To collect geographic data (continent/country where the infection was acquired) in order to evaluate regional differences in clinical treatment efficacy of 5-nitroimidazole based 1st-line treatment regimens
4. To obtain baseline stool samples for subsequent genetic analysis / resistance testing of G. lamblia isolates in cases of parasitological confirmed failure of 1st-line treatment

Study design
Prospective, observational, open-label, multi-centre study within the TropNet network.
(Note: as the drugs selected for this study are the current `gold standard´ for the treatment of giardiasis and as these drugs are licensed for this indication by the various European national health authorities it should be stressed that this study is `observational´ and not `experimental´)

Inclusion criteria
Any symptomatic person being tested positive for G. lamblia (by stool microscopy or stool antigen-test) with intestinal mono-infection is eligible for study inclusion.

Exclusion criteria
• Patients who already received giardiasis-specific treatment for the current G. lamblia infection
• Patients with asymptomatic G. lamblia infection
• Patients with concomitant bacterial, helminthic or protozoal gastrointestinal infection  (note: the presence of apathogenic protozoa [including Blastocystis hominis] is no exclusion criterion)
• Patients with contraindications (drug allergies, pregnancy, breast-feeding) for the listed drug regimens

Selected 1st-line treatment regimens under evaluation
The drug and treatment regimens chosen for evaluation within this study have been selected on the grounds of a survey conducted within the TropNet network on the currently used treatment regimen for G. lamblia (see appendix: table 1). The participating TropNet centres are free to choose among the three selected treatment regimens (according to local availability and national registration/approval of the drugs) listed below, but adherence to the specified dosage and duration of the selected regimen will be required:

Metronidazole    400 – 500mg* TID x 7 days or
Tinidazole    2g OD x 1 day or
Ornidazole    2g OD x 1 day

[TID = three times daily, OD = once daily]
Note: * the dose range of Metronidazole is based on the difference in local availability of tablets containing 400mg or 500mg respectively.

GiardiaREF: Observational multi-centre study on the efficacy of quinacrine monotherapy and albendazole-chloroquine combination therapy as 2nd-line treatment of refractory giardiasis

Background
Giardia lamblia (syn. G. duodenalis, G. intestinalis) is a flagellated protozoan that parasitizes the upper part of the small intestine of mammals, including humans, pets and livestock. Transmission occurs via the faecal-oral route by ingestion of cysts, the infective stage of the parasite, either by direct person-to-person transmission or indirectly through contaminated water and food. The clinical picture ranges from asymptomatic shedding of giardia cysts to symptomatic presentations with abdominal complaints, nausea, vomiting and acute or chronic diarrhoea. G. lamblia is considered the most common parasite causing diarrheal disease worldwide. Recently, giardiasis has been included in the ‘Neglected Disease Initiative’, estimating that 280 million people are infected worldwide with G. lamblia each year. In travellers returning  from tropical and subtropical regions G. lamblia is one of the most frequent identified aetiologies of acute and persistent diarrhoea. Among the treatment options metronidazole and other 5-nitroimidazole derivatives (tinidazole, ornidazole, secnidazole) have been the drugs of first choice for decades, while benzimidazoles, nitazoxanide, paromomycine, chloroquine, furazolidone, and quinacrine are 2nd-line therapy options – alone or in combination – in case of treatment failure (`refractory giardiasis´). Concerning the question of how to treat giardiasis, a multiplicity of studies comparing different drugs, different dosages, outcome definitions (clinical cure vs parasitological cure), treatment regimens, and as many expert opinions exist: a survey conducted among the TropNet member sites confirms the diversity of treatment regimens currently used for 1st- and 2nd-line therapy of G. lamblia throughout Europe. 53 TropNet centres reported the use of 39 different regimens including 7 different drugs given in mono- or combination therapy in various dosages and for different lengths of time.
A central issue is that most data on efficacy of drugs used for 2nd-line treatment have been obtained from studies where these drugs have been used in 1st-line therapy. The reported efficacy of 2nd-line drugs ranges from 85 to 100% for quinacrine, from 50 to 90% for albendazole, from 55% to 90% for paromomycine and from 70 to 80% for nitazoxanide. Chloroquine has been found to be as effective as metronidazole and tinidazole in 1st-line therapy of children in Cuba. The successful use of chloroquine in refractory giardiasis has frequently been reported, but good data on its overall efficacy as 2nd-line therapy is lacking. In summary, data on the efficacy of 2nd-line drugs (in mono- as well as combination regimens) for refractory giardiasis remain scarce and currently there is neither consensus nor hard evidence to recommend an optimal 2nd-line treatment regimen for refractory giardiasis.
However, some data as well as practical experience of various TropNet sites  suggest that quinacrine monotherapy is currently one of the best 2nd-line  options for refractory giardiasis. In some recent case series on refractory giardiasis, quinacrine  showed to be effective. In a treatment ladder in 38 patients with metronidazole-refractory giardiasis at our TropNet site in Bergen, Norway, metronidazole in combination with albendazole was effective in 79% (30/38), paromomycine in 50% (3/6) and quinacrine in combination with metronidazole in all 3 remaining patients who had failed the previous steps. Moreover, our TropNet site at the Hospital Clinic in Barcelona has recently published a study showing a 100% efficacy of quinacrine treatment in 14 cases of refractory giardiasis. The major problem of quinacrine as 2nd-line drug is its limited availability within Europe, which raises the question of a comparable alternative regimen.
Such an alternative regimen should ideally be highly effective, available everywhere in Europe (which is not the case of paromomycine, nitazoxanide and furazolidone) and reasonably prized (which is not the case for nitazoxanide, which is very expensive, often not covered by health insurance and therefore often not affordable for many patients). Bearing this in mind, and considering that most experts would, if quinacrine is unavailable, opt for a combination of two anti-giardia drugs with different modes of action in 2nd-line therapy, the most convenient alternative regimen would be the combination of albendazole and chloroquine .
Although all mentioned 2nd-line drugs are already used for the treatment of refractory giardiasis for years (most for decades), none of these drugs has ever (to our knowledge) formally been approved by European national health authorities for the treatment of giardiasis and their prescription in daily clinical practice remains `off-label´. As these drugs are only very infrequently needed (`orphan drugs´) there is no interest of the pharmaceutical industry to invest in expensive licensing/approval procedures and the prescription of these drugs has always been, and will most likely continue to be, `off-label´. However, the use of these drugs for the treatment of giardiasis is well established, and therefore their use – even though `off-label´ – is not `experimental´.
We initated an observational, multi-centre study within the TropNet network to evaluate the efficacy of quinacrine monotherapy and albendazole-chloroquine combination therapy as 2nd-line treatment for giardiasis (after failure of 1st-line treatment with a 5-nitroimidazole regimen). At participating TropNet sites where quinacrine is available and routinely used as 2nd-line regimen, quinacrine monotherapy will be evaluated (100mg TID for 5 days). At participating TropNet sites where quinacrine is not available, the combination of albendazole and chloroquine (albendazole 400mg + chloroquine 250mg BID for 5 days) will be evaluated.

Objectives
Main objective:
To assess the clinical and parasitological efficacy of quinacrine monotherapy and albendazole-chloroquine combination therapy for the treatment-refractory giardiasis after treatment with 5-nitroimidazole derivatives or other drugs.
Additional objectives:
1. To evaluate the tolerability of quinacrine monotherapy and albendazole-chloroquine combination therapy in the treatment of refractory giardiasis.
2. To assess treatment adherence and side-effect-related treatment cessation of quinacrine monotherapy and albendazole-chloroquine combination therapy in the treatment of refractory giardiasis.
3. To collect stool samples prior to 2nd-line treatment in order to allow subsequent genetic analysis / resistance testing of G. lamblia isolates in cases of parasitologically confirmed treatment failure of 2nd-line treatment.
4. To collect epidemiological data on the geographic background of infection.

Study design
Observational, open-label, multi-centre study within the TropNet network.

Inclusion criteria
Any person having clinically and parasitologically failed 1st-line G. lamblia treatment with a 5-nitroimidazole regimen (metronidazole, tinidazole, ornidazole, secnidazole), defined as being tested positive for G. lamblia by stool microscopy ≥2 weeks after completing medical treatment, is eligible for study inclusion. To best possible exclude cases of reinfection, the upper time limit for study inclusion will be set at 3 months after completing 1st-line treatment.
(Note: Due to the current lack of standardization, PCR-based testing for giardiasis is excluded as diagnostic or monitoring method. Giardia stool antigen test is also excluded as diagnostic method, as data on persistence of antigen in stool, leading to false positive test results despite successful treatment, is possible)

Exclusion criteria
• Patients with contraindications (drug allergies, pregnancy, breast-feeding) for the selected drug regimens.
• Female patients in child-bearing age, not able to conduct double contraception* during intake and over the `wash-out period´ of the selected study medication. The `wash-out´ period is anticipated to be equal to four half-lives of the used study drug:
  – Quinacrine: elimination half-life: ~14 days -> wash-out period 8 weeks
  – Chloroquine + albendazole: As the use of chloroquine is generally considered safe during pregnancy and breast-feeding, the wash-out period will be oriented towards the half-life of albendazole: elimination half-life of albendazole: ~12 hours -> wash-out period 2 days
• Patients having received a non-5-nitroimidazole regimen as 1st-line G. lamblia treatment.
• Patients with concomitant bacterial, helminthic or protozoal gastrointestinal infection (note: the presence of apathogenic protozoa [including Blastocystis hominis] is no exclusion criterion)

* Even though the drugs of the two selected treatment regimen have already been in clinical use for decades, it remains not completely clear, whether these treatment regimens are absolutely safe during pregnancy and breast-feeding. Therefore, study participants must use double contraception during the trial (hormonal methods (pill, coil) combined with a mechanical method such as a condom or diaphragm) until the anticipated `wash-out´ period has passed.

2nd-line treatment regimens under evaluation

Quinacrine 100mg TID for 5 days
Albendazole 400mg BID + Chloroquine 250mg BID for 5 days*

(*concomitant administration of the two drugs)