Reslizumab to Prevent Post-treatment Eosinophilia in Loiasis

• ClinicalTrials.gov Identifier: NCT01111305
• Recruitment Status: Completed
• First Posted: April 27, 2010
• Results First Posted: June 1, 2017
• Last Update Posted: December 5, 2017
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information

• First Submitted Date: April 24, 2010
• First Posted Date: April 27, 2010
• Results First Submitted Date: April 27, 2017
• Results First Posted Date: June 1, 2017
• Last Update Posted Date: December 5, 2017
• Study Start Date: April 2010
• Actual Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 30, 2017)

Change in Peak Eosinophil Count Measure as a Percent of Baseline Count. [ Time Frame: 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

• Original Primary Outcome Measures (submitted: April 24, 2010): Reduction in peak eosinophil count measure during the first 7 days of DEC treatment as a percent of baseline count. [ Time Frame: 7 days ]
• Change History: Complete list of historical versions of study NCT01111305 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: October 30, 2017)

• Frequency of AE's [ Time Frame: 7 days following initiation of DEC treatment ]
  Adverse events during the first week of DEC treatment
• Markers of Eosinophil Activation Including Levels of Eosinophil Surface Marker Expression and Serum Levels of Eosinophil Granule Proteins [ Time Frame: two years ]
• Proportion of Subjects Who Clear Blood Microfilariae [ Time Frame: 3, 7, and 28 days after initiation of treatment with DEC ]

• Original Secondary Outcome Measures (submitted: April 24, 2010): Frequency and severity of AE's, markers of eosinophil activation proportion of subjects who clear blood microfilariae and time to clearance at 3, 7, and 28 days, rate of recurrence of microfilaremia and/or clinical symptoms. [ Time Frame: 2 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Reslizumab to Prevent Post-treatment Eosinophilia in Loiasis
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

• Condition: Loiasis

Intervention

• Drug: Reslizumab
  Other Name: Cinqair
• Drug: Diethylcarbamazine
  Other Name: Hetrazan, Banocide
• Other: Placebo

Study Arms

• Active Comparator: Reslizumab + DEC
  Reslizumab 1 mg/kg iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days
  Interventions:

  • Drug: Reslizumab
  • Drug: Diethylcarbamazine
• Placebo Comparator: Placebo + DEC
  Placebo iv single dose followed by diethylcarbamazine 9 mg/kg/day po for 21 days
  Interventions:

  • Drug: Diethylcarbamazine
  • Other: Placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 3, 2015): 31
• Original Estimated Enrollment (submitted: April 24, 2010): 300
• Actual Study Completion Date: September 2017
• Actual Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)

Eligibility 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.

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01111305
• Other Study ID Numbers: 10-I-0101; 100101 ( Other Identifier: NIHCC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
• Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Not Provided

Investigators

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

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: October 2017