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

A Double-blinded, Randomized, Placebo-Controlled Dose Escalation Study to Examine the Efficacy and Microfilaricidal Kinetics and Safety of Imatinib for the Treatment of Loa Loa (A Pilot Study)

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.

Study Overview

• Status: Terminated
• Conditions: Loiasis
• Intervention / Treatment: Drug: Placebo; Drug: Imatinib Mesylate; Drug: Imatinib Mesylate; Drug: Imatinib Mesylate

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Cameroon
  • Mbalmayo, Cameroon
    • Centre de Recherche sur les Filarioses et Autres Maladies Tropicales

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subjects given vitamin placebo	Drug: Placebo; A single dose of placebo pill is given
Experimental: Imatinib 200mg; Subjects given a single dose of imatinib 200mg PO	Drug: Imatinib Mesylate; A single dose of imatinib 200mg PO is given; Other Names: Gleevec; Drug: Imatinib Mesylate; A single dose of imatinib 400mg PO is given; Other Names: Gleevec; Drug: Imatinib Mesylate; A single dose of imatinib 600mg PO is given; Other Names: Gleevec
Experimental: Imatinib 400mg; Subjects given a single dose of imatinib 400mg PO	Drug: Imatinib Mesylate; A single dose of imatinib 200mg PO is given; Other Names: Gleevec; Drug: Imatinib Mesylate; A single dose of imatinib 400mg PO is given; Other Names: Gleevec; Drug: Imatinib Mesylate; A single dose of imatinib 600mg PO is given; Other Names: Gleevec
Experimental: Imatinib 600mg; Subjects given a single dose of imatinib 600mg PO	Drug: Imatinib Mesylate; A single dose of imatinib 200mg PO is given; Other Names: Gleevec; Drug: Imatinib Mesylate; A single dose of imatinib 400mg PO is given; Other Names: Gleevec; Drug: Imatinib Mesylate; A single dose of imatinib 600mg PO is given; Other Names: Gleevec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Baseline Loa Loa Microfilariae	Percent of baseline Loa loa microfilariae as determined by concentrated peripheral blood smear. Daily measurements will be taken the first week, followed by measurements at day 14 and day 21	Days 1-7, 14, 21

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Boussinesq M, Gardon J, Gardon-Wendel N, Chippaux JP. Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon. Filaria J. 2003 Oct 24;2 Suppl 1(Suppl 1):S4. doi: 10.1186/1475-2883-2-S1-S4.
• O'Connell EM, Nutman TB. Reduction of Loa loa Microfilaremia with Imatinib - A Case Report. N Engl J Med. 2017 Nov 23;377(21):2095-2096. doi: 10.1056/NEJMc1712990. No abstract available.
• Twum-Danso NA. Loa loa encephalopathy temporally related to ivermectin administration reported from onchocerciasis mass treatment programs from 1989 to 2001: implications for the future. Filaria J. 2003 Oct 24;2 Suppl 1(Suppl 1):S7. doi: 10.1186/1475-2883-2-S1-S7.

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2019
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): March 19, 2021

Study Registration Dates

• First Submitted: December 31, 2015
• First Submitted That Met QC Criteria: December 31, 2015
• First Posted (Estimate): January 1, 2016

Study Record Updates

• Last Update Posted (Actual): June 7, 2022
• Last Update Submitted That Met QC Criteria: May 13, 2022
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Randomized; Imatinib; Cameroon; Blinded; Diethylcarbamazine; Loa loa; Filaricidal
• Additional Relevant MeSH Terms: Infections; Parasitic Diseases; Spirurida Infections; Secernentea Infections; Nematode Infections; Helminthiasis; Filariasis; Loiasis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: 999916042; 16-I-N042

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No