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 - Full Text View

Purpose

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.
DEC is the standard treatment for Loa loa infection, but it can cause mild side effects in persons with low numbers of parasites in their blood, including itchiness, muscle or joint pains, or swelling of the face or limbs. Currently, there is no way to effectively prevent these 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 helps prevent the increase of eosinophils in the blood. Giving reslizumab before DEC treatment might prevent the eosinophils from increasing and thereby might 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 infestation.
To evaluate the effect of reslizumab as part of the treatment for Loa loa infestation.

Eligibility:

Individuals between 18 and 65 years of age who have lived in or traveled to a loa-endemic region for at least 1 month. (Loa-endemic regions include northern Angola, Cameroon, Central African Republic, People s Republic of Congo, Equatorial Guinea, Gabon, Nigeria, and the Democratic Republic of Congo.)
Participants must have low numbers of parasites in the blood, as determined by the screening part of the study.

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.

Condition	Intervention	Phase
Loiasis	Drug: Reslizumab Drug: Diethylcarbamazine Other: Placebo	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Eosinophilic Disorders

Genetic and Rare Diseases Information Center resources: Lymphatic Filariasis

U.S. FDA Resources

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

Primary Outcome Measures:

Reduction in peak eosinophil count measure as a percent of baseline count. [ Time Frame: during the first 7 days of DEC treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Frequency and severity of AE's [ Time Frame: all ] [ Designated as safety issue: Yes ]
Markers of eosinophil activation including levels of eosinophil surface marker expression and serum levels of eosinophil granule proteins [ Time Frame: 12/31/16 ] [ Designated as safety issue: No ]
Proportion of subjects who clear blood microfilariae [ Time Frame: 3, 7, and 28 days after initiation of treatment with DEC ] [ Designated as safety issue: No ]


Estimated Enrollment:	300
Study Start Date:	April 2010
Estimated Study Completion Date:	May 2017
Estimated Primary Completion Date:	December 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Reslizumab	Drug: Reslizumab N/A Drug: Diethylcarbamazine N/A
Placebo Comparator: Placebo Placebo	Other: Placebo N/A

Detailed Description:

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.

Eligibility


Ages Eligible for Study:	18 Years to 65 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:

Between 18 and 65 years of age
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:

Known to be pregnant
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:

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

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

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: NCT01111305

Contacts


Contact: Nicole C Holland-Thomas, R.N.	(301) 402-5969	hollandnc@mail.nih.gov
Contact: Amy D Klion, M.D.	(301) 435-8903	aklion@niaid.nih.gov

Locations


United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 ext TTY8664111010 prpl@mail.cc.nih.gov

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators


Principal Investigator:	Amy D Klion, M.D.	National Institute of Allergy and Infectious Diseases (NIAID)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

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.

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.

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.


Responsible Party:	National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:	NCT01111305 History of Changes
Other Study ID Numbers:	100101, 10-I-0101
Study First Received:	April 24, 2010
Last Updated:	January 17, 2015
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):


Filariasis Post-Treatment Reactions Monoclonal Antibody Loa Loa Loiasis

Additional relevant MeSH terms:


Eosinophilia Hematologic Diseases Leukocyte Disorders Antibodies Diethylcarbamazine Anthelmintics Anti-Infective Agents Antinematodal Agents Antiparasitic Agents	Enzyme Inhibitors Filaricides Immunologic Factors Lipoxygenase Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Physiological Effects of Drugs Therapeutic Uses

ClinicalTrials.gov processed this record on February 26, 2015