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Efficacy and Microfilaricidal Kinetics of Imatinib for the Treatment of Loa Loa

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02644525
Recruitment Status : Active, not recruiting
First Posted : January 1, 2016
Last Update Posted : September 21, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Brief Summary:

Background:

Many people who live in west or central Africa are at risk for infection from a very small worm called Loa loa. This infection is acquired through the bite of a fly. Baby worms called microfilariae live in the blood. The infection most commonly causes skin itching, mild temporary limb swelling, and sometimes a adult worm can be seen in the white of the eye of an infected individual. Very rarely, people with this infection can develop problems with the kidneys and heart as a result of the worm s effect on the immune system. Because the vast majority of people with the infection have minimal symptoms, people in Cameroon usually do not get treated. But infection with Loa loa can cause serious problems in people who are being treated for infections with other parasites (namely, river blindness and lymphatic filariasis). Researchers want to find out of a drug called imatinib can treat Loa loa infection so that patients with this infection can safely receive other drugs to cure river blindness and lymphatic filariasis. Researchers believe imatinib can be a safe drug to use on Loa loa, because in the lab this drug kills the worms slowly, whereas other drugs which can cause treatment reactions usually kill the worms very quickly.

Objective:

To test if imatinib can treat Loa loa infection by killing the worms slowly.

Eligibility:

People ages 18-65 with non-severe Loa loa infection who are otherwise healthy

Design:

Participants will be screened with a physical exam and blood and urine tests.

Participants will have a baseline visit. This will include a physical exam and blood and urine tests. It may include a stool sample. Participants will be randomly assigned to get 1 dose of either imatinib or a placebo.

Participants will return to the clinic every day for 1 week, then once a week for 3 weeks. Visits will include a physical exam and blood tests. They will have urine tests in the first week.

Participants will have follow-up visits 3, 6, and 12 months after taking the imatinib or placebo. These include a physical exam and blood tests. They may include urine and stool samples.

If participants develop side effects, they will be treated for them.


Condition or disease Intervention/treatment Phase
Loaisis Drug: Imatinib Mesylate Drug: Placebo Phase 2

Detailed Description:
With the discovery that people experiencing severe treatment reactions following mass drug administration (MDA) with ivermectin for onchocerciasis and lymphatic filariasis control were co-infected with Loa loa, there has been a need for new filaricidal drugs. Currently, Loa loa infection, considered relatively nonpathogenic, is not treated in endemic areas. However, because treatment for Loa loa can result in toxicity in people who are being concurrently treated for onchocerciasis and lymphatic filariasis, finding a new treatment for Loa loa has become a priority. Imatinib has recently been shown to be microfilaricidal in vitro at concentrations physiologically achievable after a single oral dose in humans. The current standard in loiasis treatment outside of endemic areas is to treat those with low microfilarial (MF) levels (less than approximately 8,000MF/mL) with diethylcarbamazine (DEC). However, at high MF concentrations (>20,000 MF/mL) serious side effects including encephalopathy and death have occurred with administration of DEC or ivermectin, a widely distributed microfilaricide throughout Africa. In endemic areas, this risk is avoided by not treating loiasis altogether. The adverse reactions are believed to be due release of a large antigen load due to rapid killing of large numbers of MF. The rapidity of killing is believed to be the main driver of these reactions seen at high MF counts. The purpose of this study is to assess how imatinib acts as a slow microfilaricide at levels (<2,500 MF/mL) that have been safely treated previously with DEC and ivermectin. We aim to perform a dose escalation study to identify the minimum single oral dose that will be effective as a slow microfiaricidal drug against Loa loa. If imatinib is found to be effective and have kinetics which favor slow microfilarial killing, then this can serve as the basis for a larger study in which patients with very high microfilarial loads would be treated, as this is the at risk population in current MDA campaigns. This is a double blind, randomized, pilot phase 2 dose-escalation trial. Subjects will receive a dose of imatinib at 200, 400 or 600 (n = 5 each). Symptoms and blood microfilarial concentration will be assessed at baseline, daily for the first 7 days, then weekly for the next 21 days, then at 3, 6, and 12 months. These will be compared against an untreated placebo-controlled group of 5 subjects who will have the same data collected at these respective days.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-Blinded, Randomized, Placebo-Controlled Dose Escalation Study to Examine the Microfilaricidal Kinetics and Safety of Imatinib for the Treatment of Loa Loa (A Pilot Study)
Actual Study Start Date : September 16, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: 2
Subjects given vitamin placebo
Drug: Placebo
Placebo pills

Experimental: imatinib
Subjects given drug (200 mg, 400 mg, or 600 mg)
Drug: Imatinib Mesylate
Imatinib is a small molecule inhibitor which was US Food and Drug Administration (FDA) -approved for chronic myelogenous leukemia (CML) in 2001 which acts on the protein product of the Philadelphia chromosome, Bcr-Abl.




Primary Outcome Measures :
  1. To determine the short-term microfilaricidal kinetics of imatinib against Loa loa. [ Time Frame: 4 days ]
    Percent of baseline Loa loa microfilariae at day 4 as determined by concentrated peripheral blood smear


Secondary Outcome Measures :
  1. To assess the safety of a single dose of imatinib in Loa loa infection [ Time Frame: To determine the efficacy of single dose imatinib as a microfilaricide at 1-, 3-, 6-, and 12-month time points. ]
    Tables of adverse events by treatment group including grades of AEs, as defined by CTCAE (Common Terminology Criteria for AdverseEvents v4.0).Percent of baseline Loa loa microfilariae over time (up to 12 months).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Age greater than or equal to 18 years old and less than or equal to 65 years
    2. Loa loa microfilaremia >500 MF/mL and <2500 MF/mL at screening visit.
    3. Subject has the capacity to understand the potential risks and benefits and consents to protocol indicated blood draws and follow up visits.

EXCLUSION CRITERIA:

  1. Women under 45 years of age, or over 45 years of age with a menstrual period in the preceding 12 months.
  2. Currently breastfeeding
  3. Currently taking daily medications
  4. Known chronic medical conditions, including but not limited to diabetes, renal failure, liver disease, seizure disorder, HIV, malignancy, psychiatric disorder, or any conditions which within the investigators judgement are deemed to be clinically significant.
  5. W. bancrofti serologic positivity against Wb123
  6. O. volvulus serologic positivity against Ov16
  7. HIV by history or clinical signs of HIV/AIDS (e.g. oral thrush, oral/skin lesions of Kaposi s sarcoma, etc.)
  8. Any of the following lab abnormalities: Creatinine >1.5, Platelets <100,000/mL, Hemoglobin <12g/dL, alanine aminotransferase or aspartate aminotransferase >60 U/L, total bilirubin >1.7mg/dL, absolute neutrophil count equal to or less than 1500/mm(3).
  9. Any condition that, in the opinion of the PI, may substantially increase the risk of participation, including any contraindication to imatinib.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02644525


Locations
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Cameroon
Centre de Recherche sur les Filarioses et Autres Maladies Tropicales
Mbalmayo, Cameroon
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Elise M O'Connell, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
Publications:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02644525    
Other Study ID Numbers: 999916042
16-I-N042
First Posted: January 1, 2016    Key Record Dates
Last Update Posted: September 21, 2020
Last Verified: April 17, 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Cameroon
Filaricidal
Randomized
Blinded
Diethylcarbamazine
Additional relevant MeSH terms:
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Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action