Clinical trial NCT04115072: Treatment of Female Genital Schistosomiasis (FGS) With Praziquantel: A Proof-of-Concept Study
Official title: Treatment of Female Genital Schistosomiasis (FGS) With Praziquantel: A Proof-of-Concept Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Schistosomiasis
Keywords: Schistosomiasis
Praziquantel
Gynaecology
Female
Lead sponsor: Regionshospital Nordjylland
Sponsor class: OTHER_GOV
Collaborators: name: Charite University, Berlin, Germany
name: Leiden University Medical Center
name: Nagasaki University
name: Umeå University
name: Merck Serono International SA
name: Ministry of Health, Madagascar
First posted: 2019-10-03
Enrollment: 116
Sex: FEMALE
Minimum age (years): 15
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Female genital schistosomiasis (FGS) is a frequent manifestation of the infection with Schistosoma haematobium or mansoni. FGS is probably the most neglected gynaecological condition in the tropics.

Inflammation of genital tissue persists as long as adult worms are present in the circulation, and new eggs are released. Hence, lesions can only heal if the inflammation is abated and a normal immune response is restored

A randomized controlled study will be carried out to compare the efficacy of the standard treatment with that of five repeated doses of praziquantel.

Outcome measure is the disappearance/regression of clinical pathology at the cervix, in the vagina/vulva.

Detailed description: Female genital schistosomiasis (FGS) is a frequent manifestation of the infection with Schistosoma haematobium or mansoni. It occurs in women of all age groups, including young girls and is associated with important, frequently debilitating and stigmatizing morbidity. It may develop into a life-threatening condition. FGS is probably the most neglected gynaecological condition in the tropics.

Depending on where eggs are released the clinical pathology develops in vulva and vagina, cervix, uterus, Fallopian tubes and the ovaries. All genital organs may be affected simultaneously. Women with FGS report spontaneous, or post-coital bleeding, vaginal discharge, pain during sexual intercourse, pelvic pain, irregular menstruation and infertility. Vaginal discharge and itching, pain during sexual intercourse, spontaneous + post-coital bleeding, as well as menstruation abnormalities are attributed by the women to STIs. This results in shame, mental strain and distress, eventually causes stigmatization and social exclusion leading to an impaired life quality.

Clinical, histopathological, immunological and epidemiological evidence suggests that there is a cause-effect relationship between FGS and HIV infection. There are hints of a cause effect relationship between FGS and HPV. The association of FGS with HIV /HPV infection underlines the pivotal importance for an effective treatment of FGS.

Clinical pathology is the result of a complex inflammatory response to antigens released by adult worms and viable eggs. The inflammation of genital tissue persists as long as adult worms are present in the circulation, and new eggs are released and become trapped. Hence, lesions can only heal if the inflammation is abated and a normal immune response is restored. This means that all worms have to be eliminated and reinfection has to be prevented for some time to allow complete healing of genital organs.

Based on this rationale, five doses of praziquantel will be given over a period of 10 weeks to ensure that all existing worms will be eliminated. The first three doses aim to kill all adult worms. The fourth dose will kill schistosomula which will mature in the following weeks. The last dose will prevent women from re-infection.

A randomized controlled study will be carried out to compare the efficacy of the standard treatment with that of repeated doses of praziquantel. Since a placebo is not available, the study will not be blinded. Outcome measure is the disappearance/regression of clinical pathology at the cervix, in the vagina/vulva.

The result of this study has important implications for the sexual health of millions of women in sub-Saharan Africa.

The aim of the study is to compare standard treatment of schistosomiasis as recommended by WHO (a single dose of praziquantel 40 mg/kg)- with a treatment based on a new rationale: five doses of praziquantel 40 mg/kg

* 1 x 40 mg/kg after enrollment in the study (D1, H0) plus two single doses (40 mg/kg) after 12 and 24 hours after the first treatment
* 1 x 40 mg/kg five weeks following the 1st PZQ treatment
* 1 x 40 mg/kg ten weeks following the 1st PZQ treatment

Eligibility criteria: Inclusion Criteria:

* Women 15 to 35 years of age with a gynaecological/urinary/lower abdominal complaint
* The woman has signed the informed consent form (IFC); in the case of minors, the IFC has to be signed by parent or guardian.
* The woman does not plan to leave the area within 6 months and accept to come to the CSB regularly following the scheduled follow-up (at week 5,10 and 15).
* The woman with confirmed diagnosed of FGS (as described in section 6.3.1)
* The woman agrees to be examined clinically and gynaecologically including taking specimens from the genital tract (collection of vaginal lavage fluid, collection of cells with a cytobrush).
* The woman agrees to provide a urine and a stool sample.
* The woman agrees that a venous blood sample for laboratory assessments is taken.
* The woman accepts to stay at the hospital for 2 days follow-up after the first dose of PZQ.

Exclusion Criteria:

* Virgin (assessed by gynaecologist)
* Pregnancy (determined by pregnancy test)
* Tumor of vulva, vagina, uterus (diagnosed by gynaecologist)
* Treatment with praziquantel during the last 3 months
* Hysterectomy
* Known HIV positive prior to enrollment
* Any severe medical condition requiring hospitalization
* The woman is unable to comprehend the nature and objectives of the study
* The woman is judged by the investigators to be unlikely to participate regularly in the follow-up
* The woman is taking any drug that might affect the metabolism of PZQ and that is contraindicated the last two weeks before the enrollment. These drugs are as follows: rifampin; phenytoin, carbamazepine, phenobarbital; dexamethasone;
* The woman is taking a drug which decreases the activity of praziquantel metabolizing enzymes (P450 inhibitors) the last two weeks before the enrollment, for example cimetidine, ketoconazole, itraconazole, erythromycin.
* All contraindications to Praziquantel

Primary outcomes:
measure: Pathognomonic sign(s) in the cervix
timeFrame: 15 weeks
Secondary outcomes:
measure: Gynaecological complaint score
timeFrame: 15 weeks
measure: Vaginal Schistosome DNA
timeFrame: 15 weeks
measure: Vaginal Pro-inflammatory Th2-dependent cytokines /chemokines
timeFrame: 15 weeks
measure: Vaginal ECP
timeFrame: 15 weeks
measure: Cytobrush Schistosome DNA
timeFrame: 15 weeks
Other outcomes:
Locations:
city: Ambanja
country: Madagascar
facility: K'Olo Vanona
state: Diana
Study officials:
affiliation: Centre for Clinical Research, North Denmark Regional Hospital, Denmark
name: Peter Leutscher, PhD
role: STUDY_DIRECTOR
affiliation: K'OLO VANONA; Antananarivo, Madagascar
name: Bodo S Randrianasolo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schuster A, Randrianasolo BS, Rabozakandraina OO, Ramarokoto CE, Bronnum D, Feldmeier H. Knowledge, experiences, and practices of women affected by female genital schistosomiasis in rural Madagascar: A qualitative study on disease perception, health impairment and social impact. PLoS Negl Trop Dis. 2022 Nov 7;16(11):e0010901. doi: 10.1371/journal.pntd.0010901. eCollection 2022 Nov.
citation: Arenholt LTS, Aaroe KK, Norderud K, Lumholdt M, Randrianasolo BS, Ramarokoto CE, Rabozakandraina O, Broennum D, Feldmeier H, Leutscher PDC. Cervical lesion proportion measure using a digital gridded imaging technique to assess cervical pathology in women with genital schistosomiasis. PLoS Negl Trop Dis. 2022 Jul 5;16(7):e0009995. doi: 10.1371/journal.pntd.0009995. eCollection 2022 Jul.