Reslizumab to Prevent Post-treatment Eosinophilia in Loiasis

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01111305
• Collaborator: (none)
• Enrollment: 31
• Location: 1
• Arms: 2
• Duration (Months): 89
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Loiasis	Drug: Reslizumab; Drug: Diethylcarbamazine; Other: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Drug assignment (reslizumab vs. placebo) and eosinophil count
• 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
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Sep 1, 2017

Arms and Interventions

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	Drug: Diethylcarbamazine; Other Names: Hetrazan, Banocide ; Other: Placebo

Outcome Measures

Primary Outcome Measures

1. Peak Eosinophil Count Post-treatment [during the first 7 days of DEC treatment]

   Peak eosinophil count during the first 7 days of treatment as a percent of the baseline count

Secondary Outcome Measures

1. Frequency of AE's [7 days following initiation of DEC treatment]

   Adverse events during the first week of DEC treatment

2. Markers of Eosinophil Activation [one week]

   serum eosinophil granule protein levels on day 7 measured as % baseline

3. Proportion of Subjects Who Clear Blood Microfilariae [3, 7, and 28 days after initiation of treatment with DEC]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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;

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

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)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• 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.
• 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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01111305
• Other Study ID Numbers: 10-I-0101; 100101
• First Posted: Apr 27, 2010
• Last Update Posted: Jan 27, 2022
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Filariasis; Post-Treatment Reactions; Monoclonal Antibody; Loa Loa; Loiasis
• Additional relevant MeSH terms: Loiasis; Eosinophilia; Diethylcarbamazine; Reslizumab

Study Results

Participant Flow

Pre-assignment Detail	31 subjects were enrolled on the screening phase of this protocol, of which 13 had Loa loa infection. Of these 13, 3 were excluded for Loa loa microfilarial loads that were too high, 1 could not comply with the trial time points, and one was lost to followup. This left 8 subjects who were enrolled on the treatment portion of the study.

Arm/Group Title	Reslizumab	Placebo
Arm/Group Description	Reslizumab Diethylcarbamazine	Placebo Diethylcarbamazine
Period Title: Overall Study
STARTED	4	4
COMPLETED	4	4
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Reslizumab	Placebo	Total
Arm/Group Description	Reslizumab Diethylcarbamazine	Placebo Diethylcarbamazine	Total of all reporting groups
Overall Participants	4	4	8
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	36	29	31.5
Sex: Female, Male (Count of Participants)
Female	1 25%	1 25%	2 25%
Male	3 75%	3 75%	6 75%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 100%	4 100%	8 100%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%	4 100%	8 100%
Loa loa microfilarial level (mf/mL) [Geometric Mean (Full Range) ]
Geometric Mean (Full Range) [mf/mL]	212	357	275
Absolute eosinophil count (cells/microliter) [Geometric Mean (Full Range) ]
Geometric Mean (Full Range) [cells/microliter]	1350	710	980

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Subjects who received diethylcarbamazine treatment

Arm/Group Title	Reslizumab + DEC	Placebo + DEC
Arm/Group Description	Reslizumab 1 mg/kg iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days Reslizumab Diethylcarbamazine	Placebo iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days Diethylcarbamazine Placebo
Measure Participants	4	4
Geometric Mean (Full Range) [percent of baseline eosinophil count]	61	245.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Reslizumab + DEC, Placebo + DEC
	Comments
	Type of Statistical Test	Equivalence
	Comments	Equivalence is defined as p≥0.05
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Frequency of AE's
Description	Adverse events during the first week of DEC treatment
Time Frame	7 days following initiation of DEC treatment

Outcome Measure Data

Analysis Population Description

Subjects who received DEC treatment

Arm/Group Title	Reslizumab + DEC	Placebo + DEC
Arm/Group Description	Reslizumab 1 mg/kg iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days Reslizumab Diethylcarbamazine	Placebo iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days Diethylcarbamazine Placebo
Measure Participants	4	4
Number [adverse events]	29	28

3. Secondary Outcome

Title	Markers of Eosinophil Activation
Description	serum eosinophil granule protein levels on day 7 measured as % baseline
Time Frame	one week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Reslizumab + DEC	Placebo + DEC
Arm/Group Description	Reslizumab 1 mg/kg iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days Reslizumab Diethylcarbamazine	Placebo iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days Diethylcarbamazine Placebo
Measure Participants	4	4
% day 0 EDN at day 7	115	377
% day 0 EPO at day 7	138	203

4. Secondary Outcome

Title	Proportion of Subjects Who Clear Blood Microfilariae
Time Frame	3, 7, and 28 days after initiation of treatment with DEC

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Reslizumab	Placebo
Arm/Group Description	Reslizumab Diethylcarbamazine	Placebo Diethylcarbamazine
Measure Participants	4	4
3 days	2 50%	2 50%
7 days	4 100%	4 100%
28 days	4 100%	4 100%

Adverse Events

Time Frame	7 days
Adverse Event Reporting Description	A standardized questionnaire was used to record symptoms at every visit. Laboratory assessments were performed at every visit.
Arm/Group Title	Reslizumab + DEC		Placebo + DEC
Arm/Group Description	Reslizumab 1 mg/kg iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days Reslizumab Diethylcarbamazine		Placebo iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days Diethylcarbamazine Placebo
All Cause Mortality
	Reslizumab + DEC		Placebo + DEC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/4 (0%)
Serious Adverse Events
	Reslizumab + DEC		Placebo + DEC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Reslizumab + DEC		Placebo + DEC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		4/4 (100%)
Gastrointestinal disorders
Nausea	2/4 (50%)		1/4 (25%)
Abdominal Pain	2/4 (50%)		1/4 (25%)
General disorders
Fatigue	1/4 (25%)		3/4 (75%)
Headache	2/4 (50%)		2/4 (50%)
Investigations
LDH increased	1/4 (25%)		2/4 (50%)
ALT increased	2/4 (50%)		1/4 (25%)
AST increased	3/4 (75%)		2/4 (50%)
Bilirubin increased	1/4 (25%)		2/4 (50%)
CPK increased	2/4 (50%)		1/4 (25%)
Hematuria	2/4 (50%)		1/4 (25%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/4 (50%)		3/4 (75%)
Myalgia	2/4 (50%)		2/4 (50%)
Skin and subcutaneous tissue disorders
Calabar swelling	2/4 (50%)		1/4 (25%)
Pruritus	1/4 (25%)		2/4 (50%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.