Loiasis
Conditions
Keywords
Filariasis, Post-Treatment Reactions, Monoclonal Antibody, Loa Loa, Loiasis
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.
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.
Interventions
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Drug assignment (reslizumab vs. placebo) and eosinophil count
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion 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: 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Frequency of AE's | 7 days following initiation of DEC treatment | Adverse events during the first week of DEC treatment |
| Markers of Eosinophil Activation | one week | serum eosinophil granule protein levels on day 7 measured as % baseline |
| Proportion of Subjects Who Clear Blood Microfilariae | 3, 7, and 28 days after initiation of treatment with DEC | — |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Reslizumab Reslizumab
Diethylcarbamazine | 4 |
| Placebo Placebo
Diethylcarbamazine | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Total | Placebo | Reslizumab |
|---|---|---|---|
| Absolute eosinophil count | 980 cells/microliter | 710 cells/microliter | 1350 cells/microliter |
| Age, Continuous | 31.5 years | 29 years | 36 years |
| Loa loa microfilarial level | 275 mf/mL | 357 mf/mL | 212 mf/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 8 participants | 4 participants | 4 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 3 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 4 / 4 | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
Primary
Peak Eosinophil Count Post-treatment
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
Population: Subjects who received diethylcarbamazine treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Reslizumab + DEC | Peak Eosinophil Count Post-treatment | 61 percent of baseline eosinophil count |
| Placebo + DEC | Peak Eosinophil Count Post-treatment | 245.6 percent of baseline eosinophil count |
p-value: 0.028Wilcoxon (Mann-Whitney)
Secondary
Frequency of AE's
Adverse events during the first week of DEC treatment
Time frame: 7 days following initiation of DEC treatment
Population: Subjects who received DEC treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reslizumab + DEC | Frequency of AE's | 29 adverse events |
| Placebo + DEC | Frequency of AE's | 28 adverse events |
Secondary
Markers of Eosinophil Activation
serum eosinophil granule protein levels on day 7 measured as % baseline
Time frame: one week
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Reslizumab + DEC | Markers of Eosinophil Activation | % day 0 EDN at day 7 | 115 % change |
| Reslizumab + DEC | Markers of Eosinophil Activation | % day 0 EPO at day 7 | 138 % change |
| Placebo + DEC | Markers of Eosinophil Activation | % day 0 EDN at day 7 | 377 % change |
| Placebo + DEC | Markers of Eosinophil Activation | % day 0 EPO at day 7 | 203 % change |
Secondary
Proportion of Subjects Who Clear Blood Microfilariae
Time frame: 3, 7, and 28 days after initiation of treatment with DEC
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Reslizumab + DEC | Proportion of Subjects Who Clear Blood Microfilariae | 3 days | 2 Participants |
| Reslizumab + DEC | Proportion of Subjects Who Clear Blood Microfilariae | 7 days | 4 Participants |
| Reslizumab + DEC | Proportion of Subjects Who Clear Blood Microfilariae | 28 days | 4 Participants |
| Placebo + DEC | Proportion of Subjects Who Clear Blood Microfilariae | 3 days | 2 Participants |
| Placebo + DEC | Proportion of Subjects Who Clear Blood Microfilariae | 7 days | 4 Participants |
| Placebo + DEC | Proportion of Subjects Who Clear Blood Microfilariae | 28 days | 4 Participants |