MalariaPhase 2IVERMALNCT02511353
Efficacy and Safety of High-dose Ivermectin for Reducing Malaria Transmission: A Dose Finding Study
A Phase 2 study testing ivermectin and dihydroartemisinin-piperaquine in people with Malaria, run by Liverpool School of Tropical Medicine at 1 site in Kenya.
Trial summary
In western Kenya the prevalence of malaria in <5 year olds has fallen from 70% in 1997 to 40% in 2008, where it has now stagnated. Innovative approaches are needed to continue towards elimination. Read more about this study
- Who is it for?
- Ages 18 to 50 years
- Conditions the study is for
- Malaria
- What is being tested?
- ivermectin and dihydroartemisinin-piperaquine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 141 participants
- Where
- 1 siteKenya
- Study dates
- Jul 2015to Jul 2016
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Symptomatic, uncomplicated Plasmodium falciparum infection
- Positive malaria microscopy or malaria RDT (pLDH)
- Age: 18-50 years
- Provide written informed consent
- Agree to be able to travel to clinic on days: 1, 2, 7, 10, 14, 21, and 28
Who cannot join
- Signs or symptoms of severe malaria
- Unable to provide written informed consent
- For women: pregnancy or lactation
- Hypersensitivity to ivermectin or DP
- QTc >460 ms on ECG
- Body Mass Index (BMI) below 16 or above 32 kg/m2
Show all 13Show fewer
- Haemoglobin concentration below 9 g/dL
- Taken ivermectin in the last month
- Taken dihydroartemisinin-piperaquine in the last 12 weeks
- Loa loa as assessed by travel history to Angola, Cameroon, Chad, Central African Republic, Congo, DR Congo, Equatorial Guinea, Ethiopia, Gabon, Nigeria and Sudan
- History and/or symptoms indicating chronic illness
- Current use of tuberculosis or anti-retroviral medication
- Previously enrolled in the same study
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Efficacy and Safety of High-dose Ivermectin for Reducing Malaria Transmission: A Dose Finding Study (IVERMAL)
In western Kenya the prevalence of malaria in <5 year olds has fallen from 70% in 1997 to 40% in 2008, where it has now stagnated. Innovative approaches are needed to continue towards elimination. Ivermectin is a broad spectrum antiparasitic endectocide widely used for the control of onchocerciasis and lymphatic filariasis at a dose of 150-200 mcg/kg. Ivermectin at this dose has a potent, but short-lived effect for 6-11 days on mosquito survival, egg-laying, and parasite sporogony. Higher doses are needed to prolong its mosquitocidal effects. Previous studies have shown ivermectin is very well tolerated and safe even up to 2,000 mcg/kg. This dose finding study will evaluate the transmission blocking effect of high-dose ivermectin to define the optimal dose for future use of ivermectin in combination with artemisinin-based combination therapy (ACT) for mass drug administration (MDA). It explores a research question of global relevance. A prolonged transmission blocking effect of ivermectin could have substantial consequences for malaria control in the next decades. The results are expected to inform national malaria control programs in malaria endemic countries, to inform WHO guidelines, and to contribute to the regulatory process.
- Conditions
- Malaria
- Being tested
- ivermectin, placebo, dihydroartemisinin-piperaquine
- Keywords
- malaria, plasmodium, dihydroartemisinin-piperaquine, ivermectin
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ivermectinDrug
placeboDrug
Placebo for ivermectin.
dihydroartemisinin-piperaquineDrug
| Study group | Role | What they receive |
|---|---|---|
| placebo | Placebo comparator | Standard 3-day course of dihydroartemisinin-piperaquine, plus once a day for 3 days: placebo 600 mcg/kg/day. Receives: Drug: placebo; Drug: dihydroartemisinin-piperaquine |
| ivermectin 300 mcg/kg | Experimental | Standard 3-day course of dihydroartemisinin-piperaquine, plus once a day for 3 days: ivermectin 300 mcg/kg/day and placebo 300 mcg/kg/day. Receives: Drug: ivermectin; Drug: placebo; Drug: dihydroartemisinin-piperaquine |
| ivermectin 600 mcg/kg | Experimental | Standard 3-day course of dihydroartemisinin-piperaquine, plus once a day for 3 days: ivermectin 600 mcg/kg/day. Receives: Drug: ivermectin; Drug: dihydroartemisinin-piperaquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mosquito survival
Measured: Survival of mosquitoes at 14 days after feeding on blood taking from study participants who started the 3-day ivermectin and DP regimen 7 days earlier.
Secondary outcomes (12)
Mosquito survival
Measured: Survival of mosquitoes at each day up to day 21 or 28 after each feeding experiments performed at 0, 2 day+4h, 10, 14, 21, 28 days after start of treatment.
Number of patients with malaria clinical and parasitological treatment response
Measured: Up to day 28.
Area under the plasma concentration versus time curve (AUC) of ivermectin
Measured: Up to day 28.
Area under the plasma concentration versus time curve (AUC) of piperaquine
Dihydroartemisinin-piperaquine is a combination drug. As dihydroartemisinin has a very short elimination time, only the AUC for the longer acting piperaquine component will be determined.
Measured: Up to day 28.
Peak plasma Concentration (Cmax) of ivermectin
Measured: Up to day 28.
Peak plasma Concentration (Cmax) of piperaquine
Dihydroartemisinin-piperaquine is a combination drug. As dihydroartemisinin has a very short elimination time, only the Cmax for the longer acting piperaquine component will be determined.
Measured: Up to day 28.
Tolerability as assessed by adverse events reported in a general toxicity questionnaire
Measured: Up to day 28.
CNS adverse events
Measured: Up to day 28.
Serious adverse events
Measured: Up to day 28.
Haemoglobin concentrations
Measured: Up to day 28.
QTc interval
Measured: At 52 hours.
Mydriasis quantitated by pupillometry
Measured: Up to day 28.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jul 2015 (estimated)
- Study startJul 2015
- Primary completionJul 2016
- Study completionJul 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 141 participants (actual)
Sponsor and investigators
- Lead sponsor
- Liverpool School of Tropical Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Kenya Medical Research Institute, Centers for Disease Control and Prevention
- Responsible party
- Sponsor
- Investigators
- Menno R. Smit, MD, MPH, Principal investigator, Liverpool School of Tropical MedicineFeiko ter Kuile, Prof., Principal investigator, Liverpool School of Tropical Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02511353
- Sponsor's protocol ID
- 14.002
- Other IDs
- 2775, 6720
- Acronym
- IVERMAL
- Status last verified
- Aug 2018
- First submitted
- 15 Jul 2015
- Last updated
- 23 Aug 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Smit MR, Ochomo E, Aljayyoussi G, Kwambai T, Abong'o B, Bayoh N, Gimnig J, Samuels A, Desai M, Phillips-Howard PA, Kariuki S, Wang D, Ward S, Ter Kuile FO. Efficacy and Safety of High-Dose Ivermectin for Reducing Malaria Transmission (IVERMAL): Protocol for a Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Trial in Western Kenya. JMIR Res Protoc. 2016 Nov 17;5(4):e213. doi: 10.2196/resprot.6617.
PubMed 27856406Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Chen T, Bousema T, Slater HC, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, Ter Kuile FO. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018 Jun;18(6):615-626. doi: 10.1016/S1473-3099(18)30163-4. Epub 2018 Mar 27.
PubMed 29602751Smit MR, Ochomo EO, Waterhouse D, Kwambai TK, Abong'o BO, Bousema T, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ter Kuile FO, Ward SA, Aljayyoussi G. Pharmacokinetics-Pharmacodynamics of High-Dose Ivermectin with Dihydroartemisinin-Piperaquine on Mosquitocidal Activity and QT-Prolongation (IVERMAL). Clin Pharmacol Ther. 2019 Feb;105(2):388-401. doi: 10.1002/cpt.1219. Epub 2018 Oct 9.
PubMed 30125353Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Bousema T, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, Ter Kuile FO. Human Direct Skin Feeding Versus Membrane Feeding to Assess the Mosquitocidal Efficacy of High-Dose Ivermectin (IVERMAL Trial). Clin Infect Dis. 2019 Sep 13;69(7):1112-1119. doi: 10.1093/cid/ciy1063.
PubMed 30590537
Study at a glance
From the registry record, last updated by the sponsor on 23 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy and Safety of High-dose Ivermectin for Reducing Malaria Transmission: A Dose Finding Study (IVERMAL)
- ClinicalTrials.gov ID
- NCT02511353
- Acronym / sponsor ID
- IVERMAL / 14.002
- Conditions
- Malaria
- Keywords
- malaria, plasmodium, dihydroartemisinin-piperaquine, ivermectin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 141 participants (actual)
- Lead sponsor
- Liverpool School of Tropical MedicineUniversity, hospital or other
- Collaborators
- Kenya Medical Research Institute, Centers for Disease Control and Prevention
- Study start
- Jul 2015 (actual)
- Primary completion
- Jul 2016 (actual)
- Study completion
- Jul 2016 (actual)
- First posted
- 30 Jul 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In western Kenya the prevalence of malaria in <5 year olds has fallen from 70% in 1997 to 40% in 2008, where it has now stagnated. Innovative approaches are needed to continue towards elimination. Ivermectin is a broad spectrum antiparasitic endectocide widely used for the control of onchocerciasis and lymphatic filariasis at a dose of 150-200 mcg/kg. Ivermectin at this dose has a potent, but short-lived effect for 6-11 days on mosquito survival, egg-laying, and parasite sporogony. Higher doses are needed to prolong its mosquitocidal effects. Previous studies have shown ivermectin is very well tolerated and safe even up to 2,000 mcg/kg. This dose finding study will evaluate the transmission blocking effect of high-dose ivermectin to define the optimal dose for future use of ivermectin in combination with artemisinin-based combination therapy (ACT) for mass drug administration (MDA). It explores a research question of global relevance. A prolonged transmission blocking effect of ivermectin could have substantial consequences for malaria control in the next decades. The results are expected to inform national malaria control programs in malaria endemic countries, to inform WHO guidelines, and to contribute to the regulatory process.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| placebo | Placebo comparator | Drug: placebo, Drug: dihydroartemisinin-piperaquineStandard 3-day course of dihydroartemisinin-piperaquine, plus once a day for 3 days: placebo 600 mcg/kg/day. |
| ivermectin 300 mcg/kg | Experimental | Drug: ivermectin, Drug: placebo, Drug: dihydroartemisinin-piperaquineStandard 3-day course of dihydroartemisinin-piperaquine, plus once a day for 3 days: ivermectin 300 mcg/kg/day and placebo 300 mcg/kg/day. |
| ivermectin 600 mcg/kg | Experimental | Drug: ivermectin, Drug: dihydroartemisinin-piperaquineStandard 3-day course of dihydroartemisinin-piperaquine, plus once a day for 3 days: ivermectin 600 mcg/kg/day. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- Symptomatic, uncomplicated Plasmodium falciparum infection
- Positive malaria microscopy or malaria RDT (pLDH)
- Age: 18-50 years
- Provide written informed consent
- Agree to be able to travel to clinic on days: 1, 2, 7, 10, 14, 21, and 28
Key exclusion criteria (13 listed)
- Signs or symptoms of severe malaria
- Unable to provide written informed consent
- For women: pregnancy or lactation
- Hypersensitivity to ivermectin or DP
- QTc >460 ms on ECG
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ivermectin | Drug | ivermectin 300 mcg/kg, ivermectin 600 mcg/kg |
| placeboPlacebo for ivermectin. | Drug | ivermectin 300 mcg/kg, placebo |
| dihydroartemisinin-piperaquine | Drug | ivermectin 300 mcg/kg, ivermectin 600 mcg/kg, placebo |
Primary outcome
Mosquito survival
Time frame: Survival of mosquitoes at 14 days after feeding on blood taking from study participants who started the 3-day ivermectin and DP regimen 7 days earlier.
12 secondary outcomes
Mosquito survival
Time frame: Survival of mosquitoes at each day up to day 21 or 28 after each feeding experiments performed at 0, 2 day+4h, 10, 14, 21, 28 days after start of treatment.
Number of patients with malaria clinical and parasitological treatment response
Time frame: Up to day 28.
Area under the plasma concentration versus time curve (AUC) of ivermectin
Time frame: Up to day 28.
Area under the plasma concentration versus time curve (AUC) of piperaquine
Time frame: Up to day 28.
Peak plasma Concentration (Cmax) of ivermectin
Time frame: Up to day 28.
Peak plasma Concentration (Cmax) of piperaquine
Time frame: Up to day 28.
Tolerability as assessed by adverse events reported in a general toxicity questionnaire
Time frame: Up to day 28.
CNS adverse events
Time frame: Up to day 28.
Serious adverse events
Time frame: Up to day 28.
Haemoglobin concentrations
Time frame: Up to day 28.
QTc interval
Time frame: At 52 hours.
Mydriasis quantitated by pupillometry
Time frame: Up to day 28.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Aug 2018.
- Background: PubMed 27856406Smit MR, Ochomo E, Aljayyoussi G, Kwambai T, Abong'o B, Bayoh N, Gimnig J, Samuels A, Desai M, Phillips-Howard PA, Kariuki S, Wang D, Ward S, Ter Kuile FO. Efficacy and Safety of High-Dose Ivermectin for Reducing Malaria Transmission (IVERMAL): Protocol for a Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Trial in Western Kenya. JMIR Res Protoc. 2016 Nov 17;5(4):e213. doi: 10.2196/resprot.6617.
- Results publication: PubMed 29602751Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Chen T, Bousema T, Slater HC, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, Ter Kuile FO. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018 Jun;18(6):615-626. doi: 10.1016/S1473-3099(18)30163-4. Epub 2018 Mar 27.
- Results publication: PubMed 30125353Smit MR, Ochomo EO, Waterhouse D, Kwambai TK, Abong'o BO, Bousema T, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ter Kuile FO, Ward SA, Aljayyoussi G. Pharmacokinetics-Pharmacodynamics of High-Dose Ivermectin with Dihydroartemisinin-Piperaquine on Mosquitocidal Activity and QT-Prolongation (IVERMAL). Clin Pharmacol Ther. 2019 Feb;105(2):388-401. doi: 10.1002/cpt.1219. Epub 2018 Oct 9.
- Derived from this study: PubMed 30590537Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Bousema T, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, Ter Kuile FO. Human Direct Skin Feeding Versus Membrane Feeding to Assess the Mosquitocidal Efficacy of High-Dose Ivermectin (IVERMAL Trial). Clin Infect Dis. 2019 Sep 13;69(7):1112-1119. doi: 10.1093/cid/ciy1063.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Menno R. Smit, MD, MPH principal investigator
Liverpool School of Tropical Medicine
Feiko ter Kuile, Prof. principal investigator
Liverpool School of Tropical Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing ivermectin and dihydroartemisinin-piperaquine in people with Malaria, run by Liverpool School of Tropical Medicine at 1 site in Kenya.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Kenya. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mosquito survival (time frame: Survival of mosquitoes at 14 days after feeding on blood taking from study participants who started the 3-day ivermectin and DP regimen 7 days earlier.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02511353, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Aug 2018.