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A Systems Biology Approach to Malaria Immunity

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ClinicalTrials.gov Identifier: NCT03014258
Recruitment Status : Recruiting
First Posted : January 9, 2017
Last Update Posted : November 26, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
This is a phase I study that will assess the acquisition of immunity to Pf malaria over the course of 2-4 sequential Controlled Human Malaria Infections (CHMI) over 2-3 years, in 10 healthy adult participants. The study is expected to last for 48 months and will include 28 healthy male and female volunteers (10 active study volunteers and 18 naïve controls to confirm Pf infectivity during the 2nd -4th CHMI challenges) ages 18 to 45 years, inclusive, from the greater Baltimore community. The primary objective of this study is to determine whether protective immunity against parasite infection develops following repeat CHMI.

Condition or disease Intervention/treatment Phase
Plasmodium Falciparum Infection Biological: NF54 P. falciparum malaria challenge Phase 1

Detailed Description:
This is a phase I study that will assess the acquisition of immunity to Pf malaria over the course of 2-4 sequential Controlled Human Malaria Infections (CHMI) over 2-3 years, in 10 healthy adult participants. 10 subjects will initially be challenged with 5 uninfected mosquitoes (mock), followed by 4 challenges with 5 mosquitoes infected with drug sensitive, P. falciparum parasites (strain NF54) 2, 8, 14-20, and 20-32 months later. For the final three infective CMHIs six additional immunologic malaria-naïve subjects will be enrolled and challenged as infectivity controls. If dropouts occur within the original 10 person cohort, and two or more CHMI remain, back-up replacement volunteers will be recruited to undergo successive CHMI with the core group. All volunteers (repeat CHMI subjects and infectivity controls) will be evaluated as part of an inpatient stay to diagnose Pf malaria infection and treat with Coartem(R) (artemether/lumefantrine) or Malarone(R) (Atovaquone/proguanil). Inpatient observation will occur from Study Days 9-19 or until three-day directly observed therapy for P. falciparum infection is complete and two negative smears separated by a time interval >12 hours have been documented. A third negative smear >12 hours after the previous two inpatient smears will be documented to affirm malaria cure. The repeat CHMI subjects will have additional outpatient visits days 1, 3, 5, and 7 after the challenge to obtain blood samples to monitor the development of immunity. The study is expected to last for 48 months and will include approximately 28 healthy male and female volunteers (10 active study volunteers and 18 naïve controls to confirm Pf infectivity during the 2nd -4th CHMI challenges) ages 18 to 45 years, inclusive, from the greater Baltimore community. The primary objective of this study is to determine whether protective immunity against parasite infection develops following repeat CHMI. The secondary objectives are to: 1) determine whether clinical signs and symptoms of malaria decrease in intensity and duration following repeat CHMI, 2) identify which PBMCs are activated and proliferate on Study Days 6 and 8, treatment day and 7 days post treatment initiation or, if aparasitemic, Study Days 13 and 21 to compare responses over time and to sequential CHMI, 3) track the production of antibodies that react with P. falciparum sporozoites and blood stage parasites.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Systems Biology Approach to Malaria Immunity: Repetitive Controlled Human Malaria Infection (CHMI) Study in Malaria-Naïve Adults Using NF54 Strain Plasmodium Falciparum (Pf)
Actual Study Start Date : June 7, 2017
Estimated Primary Completion Date : November 1, 2020
Estimated Study Completion Date : November 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Active Comparator: Malaria-naïve Infectivity Control 1
1 CHMI challenge at month 8-9, n=6 immunologic malaria-naive
Biological: NF54 P. falciparum malaria challenge
Aseptically-raised A. stephensi female mosquitoes infected with aseptically-raised P. falciparum parasites of the NF54 strain.

Active Comparator: Malaria-naïve Infectivity Control 2
1 CHMI challenge at 6-12 months post-CHMI 2, n=6 immunologic malaria-naive
Biological: NF54 P. falciparum malaria challenge
Aseptically-raised A. stephensi female mosquitoes infected with aseptically-raised P. falciparum parasites of the NF54 strain.

Active Comparator: Malaria-naïve Infectivity Control 3
1 CHMI challenge at 6-12 months post-CHMI 3, n=6 immunologic malaria-naive
Biological: NF54 P. falciparum malaria challenge
Aseptically-raised A. stephensi female mosquitoes infected with aseptically-raised P. falciparum parasites of the NF54 strain.

Experimental: Repeat CHMI
1 Mock Challenge on days 1-28, followed by 4 CHMI challenges: CHMI 1 on months 2-3, CHMI 2 on months 8-9, CHMI 3 6-12 months post-CHMI 2, CHMI 4 6-12 months post-CHMI 3; N=10
Biological: NF54 P. falciparum malaria challenge
Aseptically-raised A. stephensi female mosquitoes infected with aseptically-raised P. falciparum parasites of the NF54 strain.




Primary Outcome Measures :
  1. Occurrence of a positive malaria smear [ Time Frame: Study Day 21 ]
  2. Occurrence of a positive malaria smear [ Time Frame: Study Day 29 ]
  3. Occurrence of a positive malaria smear [ Time Frame: Study Day 9 through Study Day 19 ]
  4. Occurrence of parasites using real-time quantitative PCR [ Time Frame: Study Day 21 ]
  5. Occurrence of parasites using real-time quantitative PCR [ Time Frame: Study Day 29 ]
  6. Occurrence of parasites using real-time quantitative PCR [ Time Frame: Study Day 6 through Study Day 19 ]
  7. Quantification of parasites using real-time quantitative PCR [ Time Frame: Study Day 21 ]
  8. Quantification of parasites using real-time quantitative PCR [ Time Frame: Study Day 29 ]
  9. Quantification of parasites using real-time quantitative PCR [ Time Frame: Study Day 6 through Study Day 19 ]

Secondary Outcome Measures :
  1. Occurrence of fever (> 38 degrees Celsius) attributable to malaria [ Time Frame: Study Day 6 through Study Day 29 ]
  2. Occurrence of signs and symptoms attributable to malaria (malaise, chills/rigors, nausea, vomiting, dizziness, arthralgia, abdominal pain, myalgia, and headache) [ Time Frame: Study Day 6 through Study Day 29 ]
  3. Percentage of activated effector B-cell populations [ Time Frame: 7 days after treatment initiation ]
  4. Percentage of activated effector B-cell populations [ Time Frame: Study Day 6 ]
  5. Percentage of activated effector B-cell populations [ Time Frame: Study Day 8 ]
  6. Percentage of activated effector B-cell populations in aparasitemic subjects [ Time Frame: Study Day 13 ]
  7. Percentage of activated effector B-cell populations in aparasitemic subjects [ Time Frame: Study Day 21 ]
  8. Percentage of activated effector B-cell populations in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  9. Percentage of activated effector T-cell populations [ Time Frame: 7 days after treatment initiation ]
  10. Percentage of activated effector T-cell populations [ Time Frame: Study Day 6 ]
  11. Percentage of activated effector T-cell populations [ Time Frame: Study Day 8 ]
  12. Percentage of activated effector T-cell populations in aparasitemic subjects [ Time Frame: Study Day 13 ]
  13. Percentage of activated effector T-cell populations in aparasitemic subjects [ Time Frame: Study Day 21 ]
  14. Percentage of activated effector T-cell populations in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  15. Percentage of blood stage parasites that react with antibodies [ Time Frame: 7 days after treatment initiation ]
  16. Percentage of blood stage parasites that react with antibodies [ Time Frame: Study Day 6 ]
  17. Percentage of blood stage parasites that react with antibodies [ Time Frame: Study Day 8 ]
  18. Percentage of blood stage parasites that react with antibodies in aparasitemic subjects [ Time Frame: Study Day 13 ]
  19. Percentage of blood stage parasites that react with antibodies in aparasitemic subjects [ Time Frame: Study Day 21 ]
  20. Percentage of blood stage parasites that react with antibodies in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  21. Percentage of dendritic cell populations [ Time Frame: 7 days after treatment initiation ]
  22. Percentage of dendritic cell populations [ Time Frame: Study Day 6 ]
  23. Percentage of dendritic cell populations [ Time Frame: Study Day 8 ]
  24. Percentage of dendritic cell populations in aparasitemic subjects [ Time Frame: Study Day 13 ]
  25. Percentage of dendritic cell populations in aparasitemic subjects [ Time Frame: Study Day 21 ]
  26. Percentage of dendritic cell populations in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  27. Percentage of memory B-cell populations [ Time Frame: 7 days after treatment initiation ]
  28. Percentage of memory B-cell populations [ Time Frame: Study Day 6 ]
  29. Percentage of memory B-cell populations [ Time Frame: Study Day 8 ]
  30. Percentage of memory B-cell populations in aparasitemic subjects [ Time Frame: Study Day 13 ]
  31. Percentage of memory B-cell populations in aparasitemic subjects [ Time Frame: Study Day 21 ]
  32. Percentage of memory B-cell populations in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  33. Percentage of memory T-cell populations [ Time Frame: 7 days after treatment initiation ]
  34. Percentage of memory T-cell populations [ Time Frame: Study Day 6 ]
  35. Percentage of memory T-cell populations [ Time Frame: Study Day 8 ]
  36. Percentage of memory T-cell populations in aparasitemic subjects [ Time Frame: Study Day 13 ]
  37. Percentage of memory T-cell populations in aparasitemic subjects [ Time Frame: Study Day 21 ]
  38. Percentage of memory T-cell populations in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  39. Percentage of monocyte cell populations [ Time Frame: 7 days after treatment initiation ]
  40. Percentage of monocyte cell populations [ Time Frame: Study Day 6 ]
  41. Percentage of monocyte cell populations [ Time Frame: Study Day 8 ]
  42. Percentage of monocyte cell populations in aparasitemic subjects [ Time Frame: Study Day 13 ]
  43. Percentage of monocyte cell populations in aparasitemic subjects [ Time Frame: Study Day 21 ]
  44. Percentage of monocyte cell populations in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  45. Percentage of naïve B-cell populations [ Time Frame: 7 days after treatment initiation ]
  46. Percentage of naïve B-cell populations [ Time Frame: Study Day 6 ]
  47. Percentage of naïve B-cell populations [ Time Frame: Study Day 8 ]
  48. Percentage of naïve B-cell populations in aparasitemic subjects [ Time Frame: Study Day 13 ]
  49. Percentage of naïve B-cell populations in aparasitemic subjects [ Time Frame: Study Day 21 ]
  50. Percentage of naïve B-cell populations in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  51. Percentage of naïve T-cell populations [ Time Frame: 7 days after treatment initiation ]
  52. Percentage of naïve T-cell populations [ Time Frame: Study Day 6 ]
  53. Percentage of naïve T-cell populations [ Time Frame: Study Day 8 ]
  54. Percentage of naïve T-cell populations in aparasitemic subjects [ Time Frame: Study Day 13 ]
  55. Percentage of naïve T-cell populations in aparasitemic subjects [ Time Frame: Study Day 21 ]
  56. Percentage of naïve T-cell populations in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  57. Percentage of NK cell populations [ Time Frame: 7 days after treatment initiation ]
  58. Percentage of NK cell populations [ Time Frame: Study Day 6 ]
  59. Percentage of NK cell populations [ Time Frame: Study Day 8 ]
  60. Percentage of NK cell populations in aparasitemic subjects [ Time Frame: Study Day 13 ]
  61. Percentage of NK cell populations in aparasitemic subjects [ Time Frame: Study Day 21 ]
  62. Percentage of NK cell populations in parasitemic subjects [ Time Frame: Up to Study Day 13 ]
  63. Percentage of Pf sporozoites that react with antibodies [ Time Frame: 7 days after treatment initiation ]
  64. Percentage of Pf sporozoites that react with antibodies [ Time Frame: Study Day 6 ]
  65. Percentage of Pf sporozoites that react with antibodies [ Time Frame: Study Day 8 ]
  66. Percentage of Pf sporozoites that react with antibodies in aparasitemic subjects [ Time Frame: Study Day 13 ]
  67. Percentage of Pf sporozoites that react with antibodies in aparasitemic subjects [ Time Frame: Study Day 21 ]
  68. Percentage of Pf sporozoites that react with antibodies in parasitemic subjects [ Time Frame: Up to Study Day 13 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male or non-pregnant/non-lactating female between the ages of 18 and 45 years, inclusive.
  2. Able and willing to participate for the duration of the study.
  3. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
  4. Able and willing to complete the informed consent process.
  5. Willing to donate blood for sample storage to be used for future research (Note: refusal to allow future use is exclusionary).
  6. Willing to refrain from blood donation to blood banks for 3 years following P. falciparum CHMI.
  7. Agrees not to travel to a malaria endemic region during the entire course of study participation.
  8. Physical examination and laboratory results without clinically significant findings and a body mass index (BMI) = / < 35.

    Laboratory Criteria within 56 days prior to enrollment:

  9. Hemoglobin = / >11.2 g/dL for women; = / > 12.6 g/dL for men.
  10. Platelet count within institutional normal range.
  11. Alanine aminotransferase (ALT) = / < upper limit of normal.
  12. Serum creatinine = / < upper limit of normal.
  13. Negative for HIV and Hepatitis B/C infection.

    Laboratory Criterion documented any time prior to enrollment:

  14. Negative sickle cell screening test.

    Female-Specific Criteria:

  15. Negative beta-HCG pregnancy test (serum) on day of screening or urine pregnancy test at subsequent time points for women of childbearing potential.
  16. Women of childbearing potential (exclusive of women in a same sex relationship) must agree to use effective means of birth control.* *(e.g. oral or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, abstinence, use of a condom by the sexual partner or sterile sexual partner). Women with a history of amenorrhea (> 1 year duration) or surgical or chemical sterilization (e.g. tubal ligation, hysterectomy, other) must provide written documentation of infertility from a health care provider.

Exclusion Criteria:

  1. Women who are breast-feeding or planning to become pregnant during the time interval needed to complete the study.
  2. Receipt of a malaria vaccine in a prior clinical trial.
  3. Any history of malaria infection.
  4. Evidence of increased cardiovascular disease risk; defined as > 10% five year risk by the non-laboratory method.
  5. Current use of systemic immunosuppressant pharmacotherapy.
  6. History of a splenectomy, sickle cell disease or sickle cell trait.
  7. Known history of anaphylactic response to mosquito-bites; or known allergy to artemether lumefantrine or atovaquone or proguanil or other component of the product.
  8. Participation in any study involving investigational vaccine or drug within 4 weeks prior to enrollment, or expects to receive vaccine or drug during the 2-month post-challenge period.
  9. Use or planned use of any drug with anti-malarial activity that would coincide with challenge.
  10. Anticipated use of medications known to cause drug reactions with atovaquone-proguanil (Malarone(R)) such as cimetidine, metoclopramide, antacids, and kaolin.
  11. Plans to undergo surgery (elective or otherwise) between enrollment and 4 weeks (28 days) after any of the challenges.
  12. Received a licensed vaccine within 1 month prior to enrollment in this study or expects to receive one during the 28 day post challenge period.
  13. History of psychiatric disorders or behavioral tendencies (including active alcohol or drug abuse) that in the opinion of the investigator would make compliance with the protocol difficult.* *Medical and psychiatric illness defined as personality disorders, anxiety disorders, or schizophrenia or social condition, occupational reason or other responsibility that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a volunteer's ability to give informed consent or to comply with the protocol schedule.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03014258


Contacts
Contact: Kirsten Lyke 14107060462 klyke@som.umaryland.edu

Locations
United States, Maryland
University of Maryland School of Medicine - Center for Vaccine Development - Baltimore Recruiting
Baltimore, Maryland, United States, 21201-1509
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03014258     History of Changes
Other Study ID Numbers: 15-0058
5U01AI110852-05 ( U.S. NIH Grant/Contract )
First Posted: January 9, 2017    Key Record Dates
Last Update Posted: November 26, 2018
Last Verified: March 1, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Biology
falciparum
Immunity
Infections
Malaria
Pf
Plasmodium
Systems

Additional relevant MeSH terms:
Infection
Malaria
Protozoan Infections
Parasitic Diseases