IVM Alone vs ALB + IVM Against Onchocerciasis

August 28, 2017 updated by: Christopher L. King, MD, PhD, University Hospitals Cleveland Medical Center

Comparison of Ivermectin Alone With Albendazole (ALB) Plus Ivermectin (IVM) in Their Efficacy Against Onchocerciasis

Onchocerciasis is a vector-borne nematode parasitic disease that causes severe disability. Onchocerciasis affects approximately 33 million people, mostly in 30 countries in sub-Saharan Africa (with small foci in Latin America and Yemen) 1This disease causes blindness and severe skin disease and it is spread by black flies. O. volvulus adult worms live in subcutaneous nodules. O. volvulus adult worms are larger and less sensitive to available drug treatments than those of the species that cause Lymphatic Filariasis (LF). They also have a longer lifespan (approximately 14 years rather than the estimated 7 years for LF parasites). Several programs and developments have greatly improved the Onchocerciasis. situation since the 1970's when the Onchocerciasis Control Programme (OCP) in West Africa (green countries in the map) was initiated. OCP relied exclusively on vector (black fly) control in its early years. However, following the appearance of Ivermectin (Mectizan) on the scene in the late 1980's, OCP transitioned to become a drug distribution program with annual IVM MDA in 11 countries. OCP ended in 2002. This was replaced by the African Program for Onchocerciasis Control (APOC) which coordinates community directed distribution of IVM MDA in 28 African countries (including the former OCP countries). OCP and APOC have done a good job of reducing parasite infection intensities and Onchocerciasis disease rates in many endemic countries. Unfortunately, there is no real end in sight for the APOC approach (apart from a funding endpoint in 2015); while it may be possible to eliminate Onchocerciasis. In selected areas by MDA with IVM (alone, or combined with vector control), disease control programs in most African countries will require active maintenance for many years to come. While IVR has good activity against the parasite larvae that cause disease in the skin and eye (microfilariae or Mf), it does not kill O. volvulus adult worms, and they resume production of Mf that can lead to transmission of new Onchocerciasis. Cases by black flies after a few months. APOC activities are focused on areas with high infection rates (where disease risks are highest). However, extensive areas in Africa where fewer than 20% of adult men have Onchocerciasis nodules detectable by palpation are not receiving interventions for Onchocerciasis at this time. These areas are not disease free. (Onchocerciasis dermatitis can be severe in hypoendemic areas), and they also may serve as a source for reintroduction of the parasite into previously controlled areas after interventions stop.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Onchocerciasis control programs have relied on annual MDA with IVM at a dose of 150-200 µg/kg. This regimen kills skin (and eye) Mf, thereby reducing disease and (in some areas) transmission. However, standard IVM monotherapy has little macrofilaricidal activity against adult O. volvulus, and it does not permanently sterilize adult worms, which have a reproductive life span of 12-14 years. More effective drugs or dosing schedules that have embryo-static or macrofilaricidal activity could drastically reduce the number of years required to interrupt transmission of Onchocerciasis. IVM has activity against adult O. volvulus when it is given at high doses four times per year for several years. This regimen caused some adverse events, and is not practical for national control programs. By contrast, whereas ALB has little effect on O. volvulus Mf, the drug has embryo-toxic effects at standard doses manifest as partial suppression (by 66%) of skin Mf counts for at least one year. ALB given at doses of 800 mg produced a more sustained reduction in Mf relative to a dose of 400 mg, but higher doses did not improve efficacy. It is not known whether ALB produces transient or permanent female worm sterility. Administration of a single 400 mg dose of ALB combined with IVM 200 µg/kg failed to a show greater reduction in Mf or macrofilaricidal activity compared to IVM alone; however, combination therapy suppressed embryogenesis more than IVM alone. These studies involved small numbers of participants, used ALB only at a dose of 400 mg, and followed the participants for just one year. Thus, IVM combined with ALB at higher doses given more than once per year may generate more sustained reduction in Mf by reducing female fertility or by killing adult worms.

IVM and ALB are very safe and highly effective anti-filarial drugs when given singly or in combination.

ALB causes degenerative alterations in the tegument and intestinal cells of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. The loss of cytoplasmic microtubules leads to impaired uptake of glucose by larval and adult stages of the parasite, and depletes glycogen stores. Degenerative changes in endoplasmic reticulum and mitochondria of the germinal layer, and the subsequent release of lysosomal enzymes result in decreased production of adenosine triphosphate, which is the source of energy required for survival of the helminth. Due to diminished energy production, the parasite is immobilized and eventually dies. The drug has been shown to cause occasionally (<1% of treated patients) reversible reductions in total white blood cell count. It has also been associated with slight increases in liver transaminases in ~16% of patients. The enzymes return to normal levels with cessation of treatment. These abnormalities are associated primarily with prolonged treatment for such diseases as neurocysticercosis and hydatid diseases, not single dose treatment which is being proposed here. ALB given with fatty foods as proposed in the current protocol will increase absorption and may increase the risk of adverse side effects.

IVMis an avermectin compound of macrocyclic lactones derived from the bacterium Streptomyces avermitilis. The mechanism by which IVM kills LF microfilariae is not known with certainty, but the drug interferes with glutamate gated ion channels that can affect parasite contractility and release of immunomodulatory molecules by the parasite. IVM also has a direct effect on the central nervous system and muscle function as it enhances strength of inhibitory neurotransmission pathways. The main concern with use of IVM in animals and humans is neurotoxicity, which can be manifest as ataxia. Neurotoxicity has not been observed in humans given single dose IVM for LF or other parasitic infections, and the drug has been used to treat millions of people with LF and Onchocerciasis. Peak IVM serum concentrations are reached approximately 4-5 hours after administration. The half-life of IVM in various populations ranges from 12 to 56 hours 12. There is no evidence of drug:drug interaction between ALB and IVM.

IVM can cause nausea, dizziness and occasionally pruritus, but these are infrequent, transient and usually mild. Major side effects occur with heavy infections of Loa loa; however, this parasite is not endemic in Ghana.

In Ghana the chiefs and elders are the custodians of the land so they must first to be contacted for permission to enter their communities. The study objectives and procedures are then explained to them, and if they accept it then the research team is allowed to enter the communities to explain the research aims and procedures to their subjects.

Study Type

Interventional

Enrollment (Actual)

272

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Ghana
    • Ashanti
      • Kumasi, Ashanti, Ghana
        • Committee on Human Research Publications and Ethics

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 58 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Men and women 18-60 years residing in Ashanti and Central Region of Ghana
  • ≥1 accessible nodules
  • any Mf/mg based on skin snips
  • Willingness to give informed consent to participation in the study

Exclusion Criteria:

  • Last IVM treatment < 7 months
  • Pregnant (do pregnancy test) + breastfeeding
  • Permanent disability, serious medical illnesses such as a stroke, advanced heart disease, uncontrolled diabetes, emphysema, etc that prevents or impedes study participation and/or comprehension
  • Weight of <40kg suggesting malnourishment
  • AST/ALT, γ-GT > 1.5 upper limit of normal
  • Significant glycosuria or proteinuria (2+ or 3+ protein or glucose)
  • Any one or more of the previous criteria is sufficient to exclude study participation
  • Not willing or able to give informed consent to participate in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: IVM annually (standard treatment)
The comparator (standard treatment) IVM 200 µg/kg body weight given at 0, 12 and 24 months plus vitamin pills at 6 and 18 months.
Drug: Ivermectin
Participants are either given Ivermectin alone or Ivermectin in combination with Albendazole
Experimental: IVM plus ALB twice annually
IVM 200 µg/kg plus ALB 800 mg (regardless of weight) given at 0, 6, 12, 18, 24 months
Drug: Ivermectin
Participants are either given Ivermectin alone or Ivermectin in combination with Albendazole
Drug: Albendazole
Albendazole will be given to participants in Arm 2 and 3 in combination with Ivermectin at varying time points.
Active Comparator: IVM plus ALB once annually
IVM 200 µg/kg plus ALB 800 mg given at 0, 12, 24 months plus vitamin pills at 6 and 18 months.
Drug: Ivermectin
Participants are either given Ivermectin alone or Ivermectin in combination with Albendazole
Drug: Albendazole
Albendazole will be given to participants in Arm 2 and 3 in combination with Ivermectin at varying time points.
Active Comparator: IVM twice annually
IVM 200 µg/kg given 0, 6, 12, 18, and 24 months
Drug: Ivermectin
Participants are either given Ivermectin alone or Ivermectin in combination with Albendazole

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The percent fertile female O.volvulus worms in nodules
Time Frame: 36 months
Total number of live versus dead female worms in nodules
36 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent reduction in skin Mf/mg
Time Frame: 0 months
Percent of live female worms in nodules
0 months
Percent reduction in skin Mf/mg
Time Frame: 6 months
Total number of live versus dead female worms in nodules compared to time point zero
6 months
Percent reduction in skin Mf/mg
Time Frame: 18 months
Total number of live versus dead female worms in nodules compared to time point zero
18 months
Percent reduction in skin Mf/mg
Time Frame: 36 months
Total number of live versus dead female worms in nodules compared to time point zero
36 months
Number of nodules with intact Mf
Time Frame: 36 months
number of nodules with intact Mf at 36 months following initial therapy
36 months
Soil Transmitted Helminth (STH) infections
Time Frame: 36 months
Assessment of the different treatment regimens on STH infections based on presence of intensity of ova in stools.
36 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospitals Cleveland Medical Center

Collaborators

Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2012

Primary Completion (Actual)

April 1, 2015

Study Completion (Actual)

October 1, 2016

Study Registration Dates

First Submitted

July 25, 2017

First Submitted That Met QC Criteria

July 31, 2017

First Posted (Actual)

August 3, 2017

Study Record Updates

Last Update Posted (Actual)

August 29, 2017

Last Update Submitted That Met QC Criteria

August 28, 2017

Last Verified

August 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11-11-36

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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