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| Name | Class |
|---|---|
| Walter Reed Army Institute of Research (WRAIR) | FED |
| Kenya Medical Research Institute | OTHER |
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The proposed trial design has been developed to assess the consistency and reproducibility of two consecutive direct skin feeding assays (DSFA) at 24-hour interval.
The proposed trial design has been developed to assess the consistency and reproducibility of two consecutive direct skin feeding assays (DSFA) at 24-hour interval. The results will determine the type of pivotal trial design for a follow-on Phase 2b trial whose objective is to bridge the standard membrane feeding assay (SMFA) to the direct skin feeding assay (DSFA) and direct membrane feeding assay (DMFA) using a monoclonal antibody intervention, TB31F monoclonal antibody (mAb), which interrupts transmission from human to mosquito. The results from this experimental medicine study will inform whether the preferred "Before-After" trial design in which each human volunteer serves as their own internal control can be utilized for a follow-on Phase 2b trial.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Study Volunteers | Participants provided a blood sample on Day 1 for DMFA testing and then participated in the mosquito feeding assay. On Day 2 participants underwent a second DMFA and DSFA assay (within 24 hours of the first assays). Upon completion of Day 2 DSFA participants will receive one dose of primaquine and the first dose of a 3-day regiment of artemether/lumefantrine. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Direct Skin Feeding Assay (DSFA) | Other | In the direct feeding assay a cup with 60 unfed, sterile insectary-reared Anopheles gambiae mosquitoes will be allowed to feed on a participant's calf or arm for 15 minutes. |
| Measure | Description | Time Frame |
|---|---|---|
| Oocyst Prevalence | Participants underwent feeding assays on two days, 24 hours apart (day 1 and Day 2). After feeding, mosquitoes were maintained in locked environmental chambers for 9 days to allow oocyst development. An oocyst is a structure that develops on the outer wall of the infected mosquito's stomach that contains developing sporozoites. Nine days after feeding mosquito midguts were dissected, stained with 1% mercurochrome and examined by optical microscopy. The number of oocysts in each midgut were recorded. Oocyst prevalence is defined as the percentage of mosquitoes in a cup with at least one oocyst detected in the mid-gut among the surviving mosquitoes (in the same cup) that underwent the feeding assays. | Feeding assays were performed on Day 1 and Day 2; Oocyst prevalence in surviving mosquitoes was assessed 9 days after feeding (Days 9 and 10). |
| Measure | Description | Time Frame |
|---|---|---|
| Oocyst Density | Participants underwent feeding assays on two days, 24 hours apart (Day 1 and Day 2). After feeding, mosquitoes were maintained in locked environmental chambers for 9 days to allow oocyst development. An oocyst is a structure that develops on the outer wall of the infected mosquito's stomach that contains developing sporozoites. Nine days after feeding mosquito midguts were dissected, stained with 1% mercurochrome and examined by optical microscopy. The number of oocysts in each midgut were recorded. Oocyst density is defined as the mean number of oocysts detected in infected mosquitoes that underwent feeding assays on the same participant. |
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Inclusion Criteria:
Exclusion Criteria:
Presence of any signs or symptoms of malaria
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The target sample size for subjects with gametocytemia is approximately 45 individuals. Approximately 180 participants will be screened for gametocyte carriage by PCR to achieve the target sample size. Screening of subjects will continue until the desired sample size of gametocytemic individuals who undergo all study procedures is attained. Adults aged 18 - 55 years will be recruited from the villages in the Kombewa Health and Demographics Surveillance System (HDSS) consisting of half of Kisumu
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| Name | Affiliation | Role |
|---|---|---|
| Ben Andagalu, MD | Drug Resistance Laboratory, KEMRI | Principal Investigator |
| Hoseah Akala, MD | Drug Resistance Laboratory, KEMRI | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| KEMRI | Kombewa | Kenya |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40380146 | Derived | Akala HM, Aponte JJ, Achola MA, Juma DW, Opot BH, Maisiba RN, Okoth RO, Juma JA, Mwakio EW, Mwalo MA, Oullo DO, Abuom D, Garges EC, Eyase FL, Tina LO, Copeland NK, Roth A, Mutunga J, Onyango I, Johnson J, Ogutu BR, Sifuna P, Hutter J, Mercer L, Raine M, Moore V, Ivinson K, Wu Y, Andagalu B, Ockenhouse CF. Consistency and reproducibility of independent feedings using blood from two consecutive days at varying Plasmodium falciparum gametocyte densities based on both direct membrane feeding assay and direct skin feeding assay. Malar J. 2025 May 16;24(1):154. doi: 10.1186/s12936-025-05360-3. |
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Four hundred participants consented and underwent screening. After informed consent was obtained participants were tested for the presence of mature stage malarial parasites (called gametocytes) in their blood. Forty-two participants met the inclusion criteria and were gametocyte positive and agreed to participate in the mosquito feeding assays.
Healthy adults with no malaria symptoms were recruited from the villages in the Kombewa Health and Demographics Surveillance System (HDSS) consisting of half of Kisumu West and all of Seme Sub-Counties of Kisumu County in Kenya.
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| ID | Title | Description |
|---|---|---|
| FG000 | Study Volunteers | Participants provided a blood sample on Day 1 for Direct Membrane Feeding Assay (DMFA) testing prior to participating in the Direct Skin Feeding Assay (DSFA). On Day 2 participants underwent the second DMFA and DSFA assay (within 24 hours of the first assays). Upon completion of Day 2 DSFA participants received one dose of primaquine and Coartem for 3 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Study Volunteers | Participants provided a blood sample on Day 1 for Direct Membrane Feeding Assay (DMFA) testing prior to participating in the Direct Skin Feeding Assay (DSFA). On Day 2 participants underwent the second DMFA and DSFA assay (within 24 hours of the first assays). Upon completion of Day 2 DSFA participants received one dose of primaquine and Coartem for 3 days. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Oocyst Prevalence | Participants underwent feeding assays on two days, 24 hours apart (day 1 and Day 2). After feeding, mosquitoes were maintained in locked environmental chambers for 9 days to allow oocyst development. An oocyst is a structure that develops on the outer wall of the infected mosquito's stomach that contains developing sporozoites. Nine days after feeding mosquito midguts were dissected, stained with 1% mercurochrome and examined by optical microscopy. The number of oocysts in each midgut were recorded. Oocyst prevalence is defined as the percentage of mosquitoes in a cup with at least one oocyst detected in the mid-gut among the surviving mosquitoes (in the same cup) that underwent the feeding assays. | Participants with available data; one participant did not have surviving mosquitoes in any of the assays and is not included in the analysis. The number of mosquitoes analyzed reflects the number of surviving mosquitoes after 9 days for each feeding assay and time point. | Posted | Mean | Standard Deviation | percentage of mosquitoes | Feeding assays were performed on Day 1 and Day 2; Oocyst prevalence in surviving mosquitoes was assessed 9 days after feeding (Days 9 and 10). | Mosquitoes | Mosquitoes |
2 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Study Volunteers | Participants provided a blood sample on Day 1 for Direct Membrane Feeding Assay (DMFA) testing prior to participating in the Direct Skin Feeding Assay (DSFA). On Day 2 participants underwent the second DMFA and DSFA assay (within 24 hours of the first assays). Upon completion of Day 2 DSFA participants received one dose of primaquine and Coartem for 3 days, except for two women who had a positive pregnancy test at Day 2 and did not receive primaquine. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chris F Ockenhouse, MD, PhD | PATH | +1 (202) 716-5849 | cockenhouse@path.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 7, 2021 | Dec 21, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 9, 2022 | Dec 21, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D008288 | Malaria |
| ID | Term |
|---|---|
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D000096724 | Mosquito-Borne Diseases |
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| ID | Term |
|---|---|
| D011319 | Primaquine |
| D000077611 | Artemether, Lumefantrine Drug Combination |
| ID | Term |
|---|---|
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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Sera collected will be assayed in membrane feeding assay (risk mitigation) only if gametocyte-positive subject fails to transmit any parasites to mosquitoes in either the DSFA or DMFA performed either on day 1 or day 2. Sera will be destroyed before study close-out.
| Primaquine | Drug | Participants will receive one dose of primaquine 26.3 mg tablet on Day 2 after completion of the direct feeding assay. |
|
| Artemether/Lumefantrine | Drug | Participants will receive artemether (80 mg) and lumefantrine (480 mg) combination tablets twice a day for 3 days, starting after completion of the direct feeding assay on Day 2. |
|
|
| Feeding assays were performed on Day 1 and Day 2; Oocyst density in surviving mosquitos was assessed 9 days after feeding (Days 9 and 10). |
| Sporozoite Prevalence | Participants underwent feeding assays on two days, 24 hours apart (day 1 and Day 2). After feeding, mosquitoes were maintained in locked environmental chambers for 14 days to allow sporozoite development. Sporozoites are the forms of the plasmodium that are liberated from the oocysts in the mosquito, accumulate in the salivary glands of the mosquito, and are transferred to humans when the mosquito feeds. Fourteen days after feeding, salivary glands were dissected from live mosquitoes submerged in phosphate-buffered saline (PBS) in order to visualize motile sporozoites by microscopy. Sporozoite prevalence was recorded. Sporozoite prevalence is defined as the percentage of mosquitoes in a cup with at least one sporozoite detected in the salivary glands among the mosquitoes (in the same cup) that underwent feeding assays. | Feeding assays were performed on Day 1 and Day 2; Sporozoite prevalence in surviving mosquitoes was assessed 14 days after feeding (Days 14 and 15). |
| Sporozoite Density | Sporozoite density is defined as the mean number of sporozoites detected in infected mosquitoes that underwent feeding assays. Due to limitation on the state of the art, it was not possible to estimate the sporozoite density using the Optical Microscopy technique. | Day 1 and Day 2 |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Ever had malaria? | Count of Participants | Participants |
|
| ID | Title | Description |
|---|
| OG000 | Direct Skin Feeding Assay | Each participant underwent a direct skin feeding assay on Day 1 and Day 2. |
| OG001 | Direct Membrane Feeding Assay | Blood samples from each participant were used in a direct membrane feeding assay. |
|
|
|
| Secondary | Oocyst Density | Participants underwent feeding assays on two days, 24 hours apart (Day 1 and Day 2). After feeding, mosquitoes were maintained in locked environmental chambers for 9 days to allow oocyst development. An oocyst is a structure that develops on the outer wall of the infected mosquito's stomach that contains developing sporozoites. Nine days after feeding mosquito midguts were dissected, stained with 1% mercurochrome and examined by optical microscopy. The number of oocysts in each midgut were recorded. Oocyst density is defined as the mean number of oocysts detected in infected mosquitoes that underwent feeding assays on the same participant. | Participants with available data; one participant did not have surviving mosquitoes in any of the assays and is not included in the analysis. The number of mosquitoes analyzed reflects the number of surviving mosquitos after 9 days for each feeding assay and time point. | Posted | Mean | Standard Deviation | oocysts / mosquito | Feeding assays were performed on Day 1 and Day 2; Oocyst density in surviving mosquitos was assessed 9 days after feeding (Days 9 and 10). | Mosquitoes | Mosquitoes |
|
|
|
|
| Secondary | Sporozoite Prevalence | Participants underwent feeding assays on two days, 24 hours apart (day 1 and Day 2). After feeding, mosquitoes were maintained in locked environmental chambers for 14 days to allow sporozoite development. Sporozoites are the forms of the plasmodium that are liberated from the oocysts in the mosquito, accumulate in the salivary glands of the mosquito, and are transferred to humans when the mosquito feeds. Fourteen days after feeding, salivary glands were dissected from live mosquitoes submerged in phosphate-buffered saline (PBS) in order to visualize motile sporozoites by microscopy. Sporozoite prevalence was recorded. Sporozoite prevalence is defined as the percentage of mosquitoes in a cup with at least one sporozoite detected in the salivary glands among the mosquitoes (in the same cup) that underwent feeding assays. | Participants with available data; one participant did not have surviving mosquitoes in any of the assays and is not included in the analysis. The number of mosquitoes analyzed reflects the number of surviving mosquitos after 14 days for each feeding assay and time point. | Posted | Mean | Standard Deviation | percentage of mosquitoes | Feeding assays were performed on Day 1 and Day 2; Sporozoite prevalence in surviving mosquitoes was assessed 14 days after feeding (Days 14 and 15). | Mosquitoes | Mosquitoes |
|
|
|
|
| Secondary | Sporozoite Density | Sporozoite density is defined as the mean number of sporozoites detected in infected mosquitoes that underwent feeding assays. Due to limitation on the state of the art, it was not possible to estimate the sporozoite density using the Optical Microscopy technique. | The analysis of sporozoite density could not be conducted due to technical limitations. | Posted | Day 1 and Day 2 |
|
|
| 0 |
| 42 |
| 0 |
| 42 |
| 32 |
| 42 |
| Tonsillitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Arthropod bite | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Urticaria | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
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| D000079426 |
| Vector Borne Diseases |
| D006571 | Heterocyclic Compounds |
| D000077549 | Artemether |
| D037621 | Artemisinins |
| D017382 | Reactive Oxygen Species |
| D005609 | Free Radicals |
| D007287 | Inorganic Chemicals |
| D009930 | Organic Chemicals |
| D000078102 | Lumefantrine |
| D005449 | Fluorenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D012717 | Sesquiterpenes |
| D013729 | Terpenes |
| D011083 | Polycyclic Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
|
|
| Day 2 Feeding Assay |
|
|
Comparison of DMFA Day 2 versus Day 1. |
| Poisson Regression |
| 0.003 |
Difference between days was evaluated using zero inflated Poisson regression models having as outcome the number of oocysts, as offset the number of surviving mosquitoes, and adjusted by subject. |
| Relative Rate |
| 0.23 |
| 2-Sided |
| 95 |
| 0.11 |
| 0.45 |
| Other |
|
| Day 2 Feeding Assay |
|
|
| Comparison of DMFA Day 2 versus Day 1. For each participant, the difference in sporozoite prevalence using DMFA on Day 1 versus Day 2 was estimated. To evaluate the hypothesis that the average mean difference in the prevalence between two assays within the same subject is zero, combined estimates (weighted mean and variance) were obtained using as weight the inverse of the variance of each paired difference obtained from the Agresti and Caffo method. | Other | The p-value is estimated assuming the combined difference over the square root of the weighted variance follows a normal distribution. | 0.681 | Combined Difference in Prevalence | -0.031 | 2-Sided | 95 | -0.178 | 0.117 | Other |