Reslizumab to Prevent Post-treatment Eosinophilia in Loiasis

A Randomized, Placebo-controlled, Double-Blind Pilot Study of Single-Dose Humanized Anti-IL5 Antibody (Reslizumab) for the Reduction of Eosinophilia Following Diethylcarbamazine Treatment of Loa Loa Infection

Diethylcarbamazine citrate (DEC) treatment of Loa loa infection is complicated by the development of severe adverse reactions that are correlated with the number of circulating microfilariae in the blood. The cause of these reactions is unknown, but they are accompanied by a dramatic interleukin-5 (IL-5)-dependent increase in eosinophilia and evidence of eosinophil activation. This randomized, placebo-controlled, double-blind pilot study (conducted at the NIH Clinical Center) will assess whether and to what extent the administration of reslizumab (Cinquil ), a humanized monoclonal antibody directed against IL-5, given 3 to 7 days before administration of the anthelminthic drug DEC (at 3 mg/kg 3 times daily for 21 days), prevents the development of eosinophilia in 10 adult subjects with Loa loa infection and 0-5000 microfilariae/mL. Secondary outcomes will include the severity of post-treatment effects, markers of eosinophil activation, and effects of reslizumab on microfilarial clearance.

Study Overview

• Status: Completed
• Conditions: Loiasis
• Intervention / Treatment: Other: Placebo; Drug: Reslizumab; Drug: Diethylcarbamazine

Detailed Description

Background:

Loa loa is a parasitic worm that infects people in West and Central Africa and is spread by the bite of a deerfly. Adult worms (macrofilariae) live under the skin and cause symptoms such as swellings, itching, and hives. Smaller worms (microfilariae) are found in the bloodstream. Diethylcarbamazine (DEC), the recommended medication for Loa loa infection, can produce very serious side effects, especially in people with high numbers of parasites in the blood. Researchers are investigating new treatments for Loa loa that have fewer or less serious side effects. Researchers believe that a certain kind of blood cells called eosinophils, which increase in the blood after DEC treatment, may be one of the causes of the side effects seen with DEC treatment. Reslizumab is a drug that lowers eosinophils in the blood. Giving reslizumab before DEC treatment might prevent the eosinophils from increasing and reduce some of the side effects from DEC.

Objectives:

- To determine whether reslizumab can prevent or reduce the side effects of treatment with DEC for Loa loa infection.

Eligibility:

Screening: Individuals between 18 and 65 years of age who have lived in or traveled to a Loa-endemic region for at least 1 month

Treatment study: Individuals with Loa loa infection and low numbers of parasites in the blood

Design:

This study will last 24 months and will involve several visits to the National Institutes of Health Clinical Center. Participants will be screened with a blood test for Loa loa parasites. Those who have a low number of Loa loa parasites in the blood will be asked to return for a full medical evaluation and the start of the treatment phase. Those who do not have Loa loa parasites in the blood, or those who have a high number of Loa loa parasites in the blood, are not eligible for this study treatment but may be eligible for other parasitic disease studies conducted by the National Institutes of Health.

Participants will have an initial visit with a full physical evaluation, and blood and urine tests (including leukapheresis to provide sufficient numbers of blood cells for testing). Within 1 month of the first visit, participants will have a single infusion of either reslizumab or a placebo. The infusion visit is estimated to last approximately 5 hours. Three to 7 days after the infusion, participants will begin a 21-day course of DEC (taken by mouth) to treat the infection. Participants will stay overnight at the Clinical Center during the first 3 days of treatment with DEC to be monitored for side effects, and will continue to take the DEC at home after the inpatient treatment. A study coordinator will call participants each day to ask about any symptoms or side effects. Participants will be seen for an additional eight outpatient follow-up visits (at days 7, 14, and 28, and months 3, 6, 12, 18, and 24) for evaluation of signs and symptoms of infection.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

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: (Screening)

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

1. Between 18 and 65 years of age
2. Residence in or travel to a Loa-endemic region for greater than 1 month

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
2. Known to be HIV-positive

INCLUSION CRITERIA: (Interventional Study)

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

1. The subject has documented loiasis with 0-5000 microfilariae/mL blood.
2. The subject agrees to storage of samples for study

3. A female subject is eligible for this study if she is any of the following:

   • Not pregnant or breast-feeding.
   • Of non-childbearing potential (i.e., women who have had a hysterectomy or tubal ligation or are post-menopausal, as defined by no menses in greater than or equal to 1 year)

   • Of childbearing potential but agrees to practice effective contraception* or abstinence for 3 months after administration of the investigational study drug (reslizumab or placebo)

     • NOTE: Acceptable methods of contraception may include one or more of the following: 1) male partner who is sterile prior to the female subject s entry into the study and is the sole sexual partner for the female subject; 2) implants of levonorgestrel; 3) injectable progestogen, an intrauterine device with a documented failure rate of less than 1percent; 4) oral contraceptives; and 5) double barrier methods including diaphragm or condom with a spermicide.

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. The subject tests positive for HIV infection or has any other known immunodeficiency.
2. The subject has a concomitant active infection with Onchocerca volvulus.
3. The subject has used any other investigational agent within the past 30 days.
4. The subject has used immunosuppressive agents (as listed in section 8.1) within the past 30 days.
5. The subject has a history of allergic reaction to any antibody therapy or to DEC.
6. The subject has chronic kidney or liver disease.
7. The subject has any condition that, in the Investigator s opinion, places the subject at undue risk by participating in the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Reslizumab + DEC; Reslizumab 1 mg/kg iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days	Drug: Reslizumab; Other Names: Cinqair; Drug: Diethylcarbamazine; Other Names: Hetrazan, Banocide
Placebo Comparator: Placebo + DEC; Placebo iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days	Other: Placebo; Drug: Diethylcarbamazine; Other Names: Hetrazan, Banocide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Eosinophil Count Post-treatment	Peak eosinophil count during the first 7 days of treatment as a percent of the baseline count	during the first 7 days of DEC treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of AE's	Adverse events during the first week of DEC treatment	7 days following initiation of DEC treatment
Markers of Eosinophil Activation	serum eosinophil granule protein levels on day 7 measured as % baseline	one week
Proportion of Subjects Who Clear Blood Microfilariae		3, 7, and 28 days after initiation of treatment with DEC

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Limaye AP, Abrams JS, Silver JE, Ottesen EA, Nutman TB. Regulation of parasite-induced eosinophilia: selectively increased interleukin 5 production in helminth-infected patients. J Exp Med. 1990 Jul 1;172(1):399-402. doi: 10.1084/jem.172.1.399.
• Klion AD, Massougbodji A, Sadeler BC, Ottesen EA, Nutman TB. Loiasis in endemic and nonendemic populations: immunologically mediated differences in clinical presentation. J Infect Dis. 1991 Jun;163(6):1318-25. doi: 10.1093/infdis/163.6.1318.
• Klion AD, Ottesen EA, Nutman TB. Effectiveness of diethylcarbamazine in treating loiasis acquired by expatriate visitors to endemic regions: long-term follow-up. J Infect Dis. 1994 Mar;169(3):604-10. doi: 10.1093/infdis/169.3.604.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): September 1, 2017

Study Registration Dates

• First Submitted: April 24, 2010
• First Submitted That Met QC Criteria: April 24, 2010
• First Posted (Estimate): April 27, 2010

Study Record Updates

• Last Update Posted (Actual): January 27, 2022
• Last Update Submitted That Met QC Criteria: January 20, 2022
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Monoclonal Antibody; Filariasis; Post-Treatment Reactions; Loa Loa; Loiasis
• Additional Relevant MeSH Terms: Infections; Hematologic Diseases; Parasitic Diseases; Leukocyte Disorders; Spirurida Infections; Secernentea Infections; Nematode Infections; Helminthiasis; Filariasis; Eosinophilia; Loiasis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Asthmatic Agents; Respiratory System Agents; Antiparasitic Agents; Filaricides; Antinematodal Agents; Anthelmintics; Lipoxygenase Inhibitors; Reslizumab; Diethylcarbamazine
• Other Study ID Numbers: 10-I-0101; 100101 (Other Identifier: NIHCC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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