Post-Treatment Side Effects of Ivermectin or DEC for Loa Loa Infection

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:
NCT01593722
First received: May 5, 2012
Last updated: March 14, 2014
Last verified: January 2014
  Purpose

Background:

  • Loa loa is a small worm that infects people in West and Central Africa. It is spread by the bite of a fly. Adult worms live under the skin and can cause swelling in the arms, legs, and face. Some people have more serious infections in the heart, kidneys, or brain. Most people with Loa loa infection have no symptoms at all. The standard treatment for Loa loa infection is a medicine called diethylcarbamazine (DEC). Some people have bad reactions to DEC, including itching, muscle pains, and in severe cases coma and death.
  • Another drug, ivermectin, is used in mass drug treatment programs to prevent the spread of worm infections that cause blindness and massive swelling (elephantiasis). However, people who also have Loa loa have had serious bad reactions to ivermectin. Researchers want to study both DEC and ivermectin to find out why these reactions occur. If they can be prevented, mass drug treatment programs will be able to be used in areas in Africa where Loa loa exists.

Objectives:

- To study the side effects of DEC and ivermectin treatment for Loa loa infection.

Eligibility:

- Individuals who live in 4 villages in Cameroon where Loa loa infection is known to exist, who are between 20 and 60 years of age, not pregnant or breastfeeding and have a low level of Loa loa parasites in the blood, but are otherwise healthy.

Design:

  • Participants will be screened with a physical exam and medical history. Blood samples will be collected to check for Loa loa infection. Participants will also have an eye exam and provide skin samples to check for other worm infections that may interfere with the study treatment.
  • Participants will be admitted to the hospital for 4 days (during and after the treatment). They will receive a single dose of either DEC or ivermectin.
  • After treatment, regular blood samples will be collected. Participants will be asked questions about how they feel after treatment. Physical exams will be performed. If side effects develop, participants will be treated at the hospital.
  • After leaving the hospital, participants will have followup visits. These visits will happen on days 5, 7, 9, and 14 after receiving the study medicine. They will involve a short physical exam and collection of blood samples.
  • At the end of the study, participants will be offered a full 21-day DEC treatment to cure the Loa loa infection.

Condition Intervention Phase
Loa Loa
Drug: Diethylcarbamazine
Drug: Ivermectin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Comparison Between the Post-Treatment Reactions After Single-dose Ivermectin or DEC in Subjects With Loa Loa Infection

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • The peak % change from baseline eosinophil count measured during the first 7 days post-treatment. [ Time Frame: 7 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • The frequency and severity of adverse events [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
  • Markers of eosinophil activation, including levels of surface marker expression on eosinophils and serum levels of eosinophil granule proteins [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  • Proportion of subjects who clear microfilaremia [ Time Frame: 14 days ] [ Designated as safety issue: No ]

Estimated Enrollment: 300
Study Start Date: April 2012
Study Completion Date: January 2014
Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Diethylcarbamazine
    8 mg/kg po single dose
    Drug: Ivermectin
    200 microgram/kg po single dose
Detailed Description:

Ivermectin is currently used for mass drug distribution for the control of onchocerciasis and elimination of lymphatic filariasis in Africa. Due to the occurrence of severe neurologic adverse events in individuals with concomitant Loa loa infection and high levels of circulating microfilariae, drug distribution has been halted in many areas in Cameroon, Democratic Republic of Congo and other Loa-endemic countries. Diethylcarbamazine citrate (DEC) is the treatment of choice for Loa loa infection in the United States and other non-endemic countries, but can also be associated with the development of severe adverse reactions, including fatal encephalopathy, that are correlated with the number of circulating microfilariae in the blood. The cause of these reactions is unknown, and it is not known if post-treatment reactions to DEC and ivermectin both have the same underlying mechanism. Post-treatment reactions to both medications are accompanied by a dramatic interleukin-5 (IL-5)-dependent increase in eosinophilia and evidence of eosinophil activation. Preliminary data suggests that, unlike post-treatment responses in Wolbachia-containing filariae, inflammatory mediators commonly seen in bacterial infections and malaria, including TNF-alpha and IL-1-beta, are not increased post-treatment with DEC. The aim of this study is to characterize the immunologic mechanisms of ivermectin and DEC posttreatment reactions so that it can be established whether or not these posttreatment reactions have the same underlying mechanism. An understanding of the pathophysiology of these post-treatment reactions is necessary in order to develop strategies to prevent these reactions in the future. We plan to randomize 20 subjects with low- to- moderate numbers of circulating Loa loa microfilariae to receive a single oral dose of either ivermectin (200 mcg/kg) or DEC (8 mg/kg) in an inpatient setting in Cameroon. Signs and symptoms, blood microfilarial levels, complete blood counts, intracellular and serum cytokine levels and markers of eosinophil activation will be assessed at baseline, 4 and 8 hours, and 1, 2, 3, 5, 7, and 9 and 14 days post-treatment and compared between the two treatment groups. Subjects who received ivermectin will be treated with single dose DEC (8 mg/kg) on day 14. All subjects will then be followed at 6 and 12 months post-hospitalization to determine whether they have experienced Loa-specific symptoms (eyeworm or Calabar swellings). Mf count and CBC with differential will be obtained at each follow-up visit. Subjects with Loa-specific symptoms or mf counts > 100 mf/mL at the 6 month time point will be offered a full treatment course. If > 50% of subjects meet criteria for full DEC treatment at the 6, month time point, all subjects will be treated and the study will enter a follow-up phase with a visit at 12 months (6 months after the full treatment course ).

  Eligibility

Ages Eligible for Study:   20 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA (SCREENING):

A subject will be eligible for participation in the screening portion of this protocol if all of the following criteria apply:

  1. male or non-pregnant and not breastfeeding female subjects,
  2. age 20-60 years (per participant self-report)
  3. resident of Akonolinga
  4. Loa microfilaremia from 20 to 5000 mf/mL from the prior screening in the village or did not participate in the prior screening
  5. consent to a blood draw to screen for infection with Loa loa
  6. must be willing to have blood samples stored

EXCLUSION CRITERIA (SCREENING):

A subject will not be eligible for participation in the screening portion of this study if any of the following conditions apply:

  1. Known to be pregnant (by history) or breastfeeding
  2. Chronic medical conditions, including but not limited to diabetes, renal or hepatic insufficiency, immunodeficiency, psychiatric disorder, seizure, that in the investigators judgments are deemed to be clinically significant
  3. History of hypersensitivity reaction to DEC or IVM

INCLUSION CRITERIA (INTERVENTIONAL STUDY):

A subject will be eligible for participation in the interventional portion of the study only if all of the following additional inclusion criteria apply:

  1. Loa loa microfilaremia between 20 and 2,000 mf/mL blood drawn between 11:30 am and 2:30 pm measured within 30 days prior to the baseline visit
  2. The subject agrees to storage of samples for study

EXCLUSION CRITERIA (INTERVENTIONAL STUDY):

A subject will not be eligible to participate in the interventional portion of the study if any of the following conditions are fulfilled at the time of enrollment:

  1. Pregnancy (by serum or urine beta-HCG) or breastfeeding
  2. Chronic kidney or liver disease
  3. Hgb < 10 gm/dL
  4. Filarial infection other than Loa loa or M. perstans (O. volvulus, or W. bancrofti)
  5. Use of DEC or IVM within the past 6 months
  6. Use of immunosuppressive therapies, including steroids, within the past month
  7. Any condition that in the investigator s opinion places the subject at undue risk by participating in the study

EXCLUSION OF CHILDREN AND PREGNANT WOMEN:

Pregnant women and children (the age of consent in Cameroon is 20 years of age) will be excluded from this study since it involves administration of medications contraindicated in pregnancy and more than minimal risk with no prospect of direct benefit, respectively.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01593722

Locations
Cameroon
Filariasis and other Tropical Diseases Research Center
Yaounde, Cameroon
Sponsors and Collaborators
Investigators
Principal Investigator: Amy D Klion, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier: NCT01593722     History of Changes
Other Study ID Numbers: 999912117, 12-I-N117
Study First Received: May 5, 2012
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Loiasis
Immune Response
Therapy

Additional relevant MeSH terms:
Ivermectin
Diethylcarbamazine
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Filaricides
Antinematodal Agents
Anthelmintics
Lipoxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 02, 2014