In-vivo Transmission Model in Semi-immune Adults

NCT06172686 | Unknown Phase 1

• 1 other identifier: Blood-CHMI Trans
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

Controlled human malaria infection (CHMI) has revolutionized the development of malaria vaccines. It involves the administration of either known numbers of sporozoites or infected erythrocytes to healthy human volunteers under a controlled environment. The use of highly sensitive molecular malaria diagnostic methods informs treatment decisions before symptom development and allows the characterization of parasite growth dynamics. Sporozoite CHMI has safely been used in six countries in Africa providing a platform to assess the efficacy of candidate malaria vaccines and study the natural immunity to malaria. Blood stage CHMI involves administration of known number of Artemether Lumefantrine sensitive infected erythrocytes in healthy volunteers, and it is a more sensitive model for modelling parasite growths and study the efficacy of blood-stage malaria vaccines. It has been safely used in Australia and Europe but not in Africa. Adaptation of this model by administration of combination of suboptimal and optimal antimalarial drugs lead to increased gametocytaemia, and infection rates in mosquitoes following standard membrane feeding assay. Such adaptation allows the model to be used to study parasite transmission from human to mosquitoes and evaluate transmission blocking malaria interventions. There is an urgent need to establish an in vivo model for early-stage clinical evaluation of transmission blocking interventions (TBI) in volunteers living in malaria endemic countries. This would allow rapid and cost-effective way to down-select transmission blocking candidate malaria vaccine and gametocidal antimalarial drugs before larger, more complex, and expensive field efficacy studies are conducted. A study done in naïve individual showed 100% success in establishing a malaria infection using 2800 P. falciparum infected RBCs, while a recent study (manuscript in development) has demonstrated success in establishing infection in Tanzanian semi-immune individuals with low malaria exposure using 1000 P. falciparum infected RBCs. We will use 1000 ALU-sensitive 3D7 P. falciparum infected RBCs to establish an in vivo transmission model for studying Transmission blocking interventions and assess the efficiency of two antimalarial drugs regimens (Piperaquine and doxycycline) to induce high levels of gametocytaemia and mosquito infection rates in healthy African adults. We will also investigate the determinants of successful transmission to mosquitoes including underlying immune responses to both asexual and sexual malaria antigens, asexual parasite dynamics and gametocyte burden, sex ratio of male and female gametocytes, and the relationship between gametocyte density and mosquito infection rate

Conditions

Controlled Human Malaria Infection; Induced Blood Stage Malaria Infection; Malaria Transmission; Malaria Challenge

Outcome Measures

Primary Outcomes (2)

• Solicited and unsolicited adverse events

  Frequency of solicited and unsolicited adverse events.

  Up to day 98 after blood infection challenge.

• Magnitude of Adverse Events

  Magnitude of Adverse Events both solicitated and Unsolicited

  Up to day 98 after blood infection challenge.

Secondary Outcomes (7)

• Rate of Mosquito infections (proportion of infected mosquitoes)

  14, 21 and 28 days after infection challenge

• Infection burden (Oocysts density in infected mosquitoes)

  14, 21 and 28 days after infection challenge

• Number of volunteers in each study arm that show prevalence of gametocytes as defined by quantitative reverse-transcriptase PCR (qRT-PCR) for CCp4 (female) and pfMGET (male) mRNA with a threshold of 5 gametocytes/mL for positivity.

  Up to day 28 after blood infection challenge

• Time to peak density gametocytes from the time of challenge as measured by qRT-PCR.

  Up to day 28 after the blood infection challenge

• The area under the curve of gametocyte density versus time for both arms of the study

  Up to day 28 after the blood infection challenge

Study Arms (2)

Arm1

EXPERIMENTAL

The first arm will receive Piperaquine tablets , that will be administered orally. Sub-curative regimen will be given as two tablets of 320mg and 160mg (total of 480mg).

Drug: Piperaquine tablets , which will be administered orally as a single dose of 480mg (320mg+160mg).

Arm 2

EXPERIMENTAL

The second arm will receive Doxycycline (100mg tablets strength as Doxycycline hyclate) that will also be administered orally. Sub-curative regimen will be given as 1 tablet (100mg) once daily for 7 days.

Drug: Doxycycline (100mg tablets strength as Doxycycline Hyclate) will also be administered orally and will be given as 1 tablet (100mg) Once daily for 7 days.

Interventions

Piperaquine tablets , which will be administered orally as a single dose of 480mg (320mg+160mg). DRUG

The first arm will receive Piperaquine tablets, that will be administered orally. Sub-curative regimen will be given as two tablets of 320mg and 160mg (total of 480mg).

Arm1

Doxycycline (100mg tablets strength as Doxycycline Hyclate) will also be administered orally and will be given as 1 tablet (100mg) Once daily for 7 days. DRUG

The second arm will receive Doxycycline (100mg tablets strength as Doxycycline hyclate) that will also be administered orally. Sub-curative regimen will be given as 1 tablet (100mg) once daily for 7 days.

Arm 2

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male volunteers aged 18-45 years and in good health.
• Volunteer has adequate understanding of the procedures of the study and is able and willing (in the investigator's opinion) to comply with all study requirements.
• Participant is willing and able to give informed consent for participation in the trial.
• Participant with low malaria exposure as determined by anti-schizont ELISA
• Literacy in Kiswahili.
• Anti-schizont antibody levels below 50th centile of the most recently available population anti-schizont in Bagamoyo district

You may not qualify if:

• Any history, or evidence at screening, of clinically significant symptoms, physical signs or abnormal laboratory values suggestive of systemic conditions, such as cardiovascular, pulmonary, gastrointestinal, renal, hepatic, neurological, dermatological (e.g. psoriasis, contact dermatitis etc.), allergy, endocrine, malignant, haematological, infectious, immunodeficient, psychiatric and other disorders, which could compromise the health of the volunteer during the study or interfere with the interpretation of the study results.
• A heightened risk of cardiovascular disease, as determined by: an estimated ten-year risk of fatal cardiovascular disease of ≥5% at screening, as determined by the Systematic Coronary Risk Evaluation (SCORE); history, or evidence at screening, of clinically significant arrhythmia, prolonged QT-interval or other clinically relevant ECG abnormalities; or a positive family history of cardiac events in 1st or 2nd degree relatives \<50 years old.
• Body mass index (BMI) of \<18 or \>30 Kg/m2
• A medical history of functional asplenia
• Female volunteers
• Confirmed parasite positive by PCR a day before challenge i.e., at C-1.
• Screening tests positive for Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV)
• Chronic use (\>30 days) of i) immunosuppressive drugs, ii) antibiotics, iii) or other immune modifying drugs within three months prior to study onset (inhaled and topical corticosteroids and oral antihistamines exempted) or expected use of such during the study period
• Any recent (within 30 days) or current systemic therapy with an antibiotic or drug with potential antimalarial activity (chloroquine, doxycycline, tetracycline, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, erythromycin, hydroxychloroquine, etc.) (Allowable time frame for use at the Investigator'sdiscretion).
• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years.
• Any history of treatment for severe psychiatric disease by a psychiatrist in the past year.
• History of drug or alcohol abuse interfering with normal social function in the period of one year prior to study onset.
• Previous participation in any malaria investigational product study (allowable time frame for use at the Investigator's discretion)
• Participation in any other clinical study in the 30 days prior to the start of the study or during the study period.
• Being an employee or relative of an employee of Ifakara Health Institute.

Sponsors & Collaborators

• Ifakara Health Institute: lead
• University of Oxford: collaborator

Study Sites (1)

Ifakara Health Institute

Pwani, Tanzania

Location

Related Publications (9)

• Aregawi MW, Ali AS, Al-mafazy AW, Molteni F, Katikiti S, Warsame M, Njau RJ, Komatsu R, Korenromp E, Hosseini M, Low-Beer D, Bjorkman A, D'Alessandro U, Coosemans M, Otten M. Reductions in malaria and anaemia case and death burden at hospitals following scale-up of malaria control in Zanzibar, 1999-2008. Malar J. 2011 Feb 18;10:46. doi: 10.1186/1475-2875-10-46.

  PMID: 21332989 BACKGROUND

• Ceesay SJ, Casals-Pascual C, Nwakanma DC, Walther M, Gomez-Escobar N, Fulford AJ, Takem EN, Nogaro S, Bojang KA, Corrah T, Jaye MC, Taal MA, Sonko AA, Conway DJ. Continued decline of malaria in The Gambia with implications for elimination. PLoS One. 2010 Aug 18;5(8):e12242. doi: 10.1371/journal.pone.0012242.

  PMID: 20805878 BACKGROUND

• Farnert A, Yman V, Homann MV, Wandell G, Mhoja L, Johansson M, Jesaja S, Sandlund J, Tanabe K, Hammar U, Bottai M, Premji ZG, Bjorkman A, Rooth I. Epidemiology of malaria in a village in the Rufiji River Delta, Tanzania: declining transmission over 25 years revealed by different parasitological metrics. Malar J. 2014 Nov 26;13:459. doi: 10.1186/1475-2875-13-459.

  PMID: 25423887 BACKGROUND

• Okiro EA, Hay SI, Gikandi PW, Sharif SK, Noor AM, Peshu N, Marsh K, Snow RW. The decline in paediatric malaria admissions on the coast of Kenya. Malar J. 2007 Nov 15;6:151. doi: 10.1186/1475-2875-6-151.

  PMID: 18005422 BACKGROUND

• Assele V, Ndoh GE, Nkoghe D, Fandeur T. No evidence of decline in malaria burden from 2006 to 2013 in a rural Province of Gabon: implications for public health policy. BMC Public Health. 2015 Feb 4;15:81. doi: 10.1186/s12889-015-1456-4.

  PMID: 25649228 BACKGROUND

• Okiro EA, Bitira D, Mbabazi G, Mpimbaza A, Alegana VA, Talisuna AO, Snow RW. Increasing malaria hospital admissions in Uganda between 1999 and 2009. BMC Med. 2011 Apr 13;9:37. doi: 10.1186/1741-7015-9-37.

  PMID: 21486498 BACKGROUND

• Holden JD. Benefits and risks of childhood immunisations in developing countries. Br Med J (Clin Res Ed). 1987 May 23;294(6583):1329-31. doi: 10.1136/bmj.294.6583.1329.

  PMID: 3109642 BACKGROUND

• Robertson RL, Foster SO, Hull HF, Williams PJ. Cost-effectiveness of immunization in The Gambia. J Trop Med Hyg. 1985 Oct;88(5):343-51.

  PMID: 3939146 BACKGROUND

• Miura K, Swihart BJ, Deng B, Zhou L, Pham TP, Diouf A, Burton T, Fay MP, Long CA. Transmission-blocking activity is determined by transmission-reducing activity and number of control oocysts in Plasmodium falciparum standard membrane-feeding assay. Vaccine. 2016 Jul 29;34(35):4145-4151. doi: 10.1016/j.vaccine.2016.06.066. Epub 2016 Jun 29.

  PMID: 27372156 BACKGROUND

Related Links

• World Health O. World malaria report 2019. Geneva: World Health Organization; 2019 2019

MeSH Terms

Interventions

piperaquine; Doxycycline

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Ally Olotu, MD,Dphil

  Ifakara Health Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ally Olotu, MD,Dphil

CONTACT

+255 718 927 104; aolotu@ihi.or.tz

Enock kessy, BSc,MSc

CONTACT

+255 626 837 898; ekessy@ihi.or.tz

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Two antimalarial drugs will be used to induce gametocytes. The first arm will receive Piperaquine tablets (Piramal Pharma Solutions, India), that will be administered orally. Sub-curative regimen will be given as two tablets of 320mg and 160mg (total of 480mg). The second arm will receive Doxycycline (100mg tablets strength as Doxycycline hyclate) that will also be administered orally. Sub-curative regimen will be given as 1 tablet (100mg) once daily for 7 days.

Study Record Dates

• First Submitted: December 7, 2023
• First Posted: December 15, 2023
• Study Start: January 9, 2024
• Primary Completion: February 13, 2024
• Study Completion: June 30, 2024
• Last Updated: December 15, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: within 12 months after study completion
• Access Criteria: Open access

Locations

TA (1)