Efficacy and Safety of IVM/ALB Co-administration
Condition: Trichuriasis
MeSH terms: Trichuriasis
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      This study is a double-blind randomized clinical trial conducted with two settings in Africa
      and one in Asia, namely Côte d'Ivoire, Pemba (Zanzibar, Tanzania) and Lao PDR. This study
      aims at providing evidence on the efficacy and safety of co-administered albendazole and
      ivermectin versus albendazole monotherapy (standard of care) against whipworm (T. trichiura)
      infections in children and adults (6-60 years).

      The efficacy of the treatment and potential extended effects on follow-up prevalence will be
      determined 14-21 days, 6 months and 12 months post-treatment by collecting another two stool
      samples. The cure rate will be calculated as the percentage of egg-positive subjects at
      baseline who become egg-negative after treatment.
    

Detailed description: 
      This study is a double-blind randomized clinical trial which aims at providing evidence on
      the efficacy and safety of co-administered albendazole and ivermectin versus albendazole
      monotherapy (standard of care) against T. trichiura infections in children and adults (6-60
      years) in different transmission settings and geographies. Embedded in this trial a smaller
      dose-finding (DF) study with the goal to investigate efficacy, safety and pharmacokinetic
      parameters of ascending doses of ivermectin ((i) 200 µg/kg, (ii) 400 µg/kg, and (iii) 600
      µg/kg) co-administered with albendazole (400 mg) in school-aged children infected with T.
      trichiura will take place.

      The primary objective of the trial is to comparatively assess the efficacy in terms of cure
      rate against T. trichiura infections among school-aged children and adults from three
      different epidemiological settings and monitored over a 12-month period of
      albendazole/ivermectin combination therapy and albendazole monotherapy. A DF study will be
      implemented in the trial with the objective to understand the dose-dependent efficacy and
      pharmacokinetic profile of the co-administration of albendazole and ivermectin in school-aged
      children (6-12 years) with the following four oral treatment regimens: i) albendazole (400
      mg) /ivermectin (200 µg/kg) combination, ii) albendazole (400 mg) /ivermectin (400 µg/kg)
      combination, iii) albendazole (400 mg) /ivermectin (600 µg/kg) combination, and iv) placebo.

      The secondary objectives of the trial are to evaluate the safety and tolerability of the
      treatment regimens, compare the ERRs of the treatment regimens (combination vs. monotherapy
      and ascending doses of the combination) against T. trichiura, determine the CRs and ERRs of
      the drugs in study participants (6-60 years) infected with hookworm, A lumbricoides and S
      stercoralis, investigate potential extended effects on follow-up helminth prevalences (6 and
      12 months post-treatment) of the two standard-dose treatment regimens (as assessed among
      participants with cleared infection on days 21 and 180), compare CRs based on infection
      status determined by novel polymerase chain reaction (PCR)-based and standard microscopic
      diagnosis, assess potential differences in susceptibility to the treatment regimen between
      the three hookworm species, Necator americanus, Ancylostoma duodenale and A. ceylanicum, as
      classified through the novel PCR-based diagnosis, characterize T. trichiura strains from
      different epidemiological settings through genotyping, evaluate potential benefits from
      deworming on morbidity (clinically evaluated and self-rated from questionnaire interviews)
      and nutritional indicators, and determine an exposure (including length of time that the drug
      concentration is above the minimal inhibitory concentration (MIC), Cmax, area under the curve
      (AUC))-response correlation of ivermectin and albendazole in school-aged children.

      After obtaining informed consent from individual/parents and/or caregiver, the medical
      history of the participants will be assessed with a standardized questionnaire, in addition
      to a clinical examination carried out by the study physician before treatment. Enrollment
      will be based on two stool samples will be collected, if possible, on two consecutive days or
      otherwise within a maximum of 5 days. All stool samples will be examined with duplicated
      Kato-Katz thick smears by experienced laboratory technicians.

      Randomization of participants into the two treatment arms will be stratified according to
      intensity of infection. All participants will be interviewed before treatment, 3 and 24 hours
      and 3 weeks after treatment about the occurrence of adverse events. Children aged 6-16 years
      will additionally be asked to rate their own physical functioning by replying to a pre-tested
      questionnaire at baseline and 6 and 12 months after treatment. The efficacy of the treatment
      and potential extended effects on follow-up prevalence will be determined 14-21 days, 6
      months and 12 months post-treatment by collecting another two stool samples. Subjective
      treatment satisfaction will be assessed 3 hours, 3 weeks and 6 months after treatment to
      investigate relationship with treatment compliance and observed efficacy in reducing egg
      output and morbidity.

      The primary analysis will include all participants with primary end point data (available
      case analysis). Supplementary, a per-protocol analysis will be conducted. CRs will be
      calculated as the percentage of egg-positive subjects at baseline who become egg-negative
      after treatment. Differences among CRs (between treatment arms and between diagnostic
      approaches) will be analysed by using crude and adjusted logistic regression modeling
      (adjustment for age, sex and weight).

      Geometric and arithmetic mean egg counts will be calculated for the different treatment arms
      before and after treatment to assess the corresponding ERRs. Bootstrap resampling method with
      5,000 replicates will be used to calculate 95% confidence intervals (CIs) for differences in
      ERRs.
    

Intervention name(s): Albendazole; Albendazole and Ivermectin
Intervention type(s): Drug; Drug
Intervention description(s): Monotherapy of albendazole (400 mg); Combination therapy of albendazole (400 mg) and ivermectin (200 µg/kg)
Other intervention name(s): Zentel®; Zentel® and Stromectol®
Intervention MeSH terms: Ivermectin; Albendazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment