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MalariaPhase 2NCT03278808

Chloroquine (CQ) and Azithromycin (AZ) Combination for Malaria Prophylaxis

A Phase 2 study testing Chloroquine-Azithromycin (CQ/AZ), Chloroquine (CQ) and atovaquone-proguanil (Malarone®) in people with Malaria, run by U.S. Army Medical Research and Development Command at 2 sites in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
Search all trials

Trial summary

This is an open label, Phase 2 study with controlled human malaria infection (CHMI). Twenty three subjects will be enrolled into 2 groups (15 subjects in the Chloroquine-Azithromycin [CQ/AZ] Intervention Group, and 8 subjects in the Chloroquine [CQ] Group). Read more about this study

Who is it for?
Ages 18 to 50 yearsHealthy volunteers can take part
Conditions the study is for
Malaria
What is being tested?
Chloroquine-Azithromycin (CQ/AZ), Chloroquine (CQ) and atovaquone-proguanil (Malarone®)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
2 sitesUnited States
Study dates
17 Sep 2018to 1 Jan 2020
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
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • Healthy adults (male or non-pregnant, non-lactating female) 18 to 50 years of age (inclusive) at the time of screening.
  • If the subject is female:
  • Non-childbearing potential (ie., either surgically sterilized (bilateral tubal ligation, tubes tied, hysterectomy, removal of the uterus, bilateral oophorectomy, removal of both ovaries) at least 6 months before dosing) or one year post menopausal), abstinent or using adequate contraceptive precautions (eg, intrauterine contraceptive device; oral contraceptives; diaphragm, cervical cap, or condom in combination with contraceptive jelly, cream or foam; Norplant® or Depo-Provera®) from 3 months prior to this study through 56 days after challenge
  • A negative pregnancy test at the time of enrollment
  • Free of significant health problems as established by medical history, laboratory, and clinical examination before entering the study
  • Subjects must have low cardiac risk factors according to the NHANES I criteria, medical history and family history, blood pressure measurements, and a normal or normal variant ECG including QTcF no greater than 450 msec for males and 470 msec for females.
Show all 14Show fewer
  • Available to participate in all planned study visits and reachable by phone for duration of study (approximately 4 months).
  • Willing to comply with all protocol procedures and time commitments
  • No plans to participate in another clinical research study for the duration of this study.
  • Written informed consent must be obtained from the subject before screening procedures are performed
  • If a subject is active duty military, he or she must obtain approval from his or her supervisor per Walter Reed Army Institute of Research (WRAIR) Policy 11-45
  • Subjects must score at least 80% correct on a multiple-choice quiz that assesses their understanding of this study
  • If they do not score 80% on the initial quiz, the protocol information will be reviewed with them, and they will have the opportunity to retest
  • If a subject fails to correctly answer 80% of the questions after 2 attempts, he or she will be excluded from the study

Who cannot join

  • Subjects with a history or presence of gastrointestinal, hepatic or renal disease, or other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs.
  • Subjects with a history of retinopathy, sickle cell disease or trait, psoriasis, or porphyria.
  • Subjects who take certain prescribed or over the counter (OTC) concomitant medication including: ampicillin, antacids (including kaolin), cimetidine, digoxin, ergot alkaloids, statins (HMG-CoA reductase inhibitors), cyclosporine, warfarin, fluconazole, nelfinavir, or rifabutin, within 2 weeks of dosing start, and during the duration of the study.
  • Are known or suspected of drinking too much alcohol (for men, more than 28 standard alcohol drinks and for women more than 21 standard alcohol drinks per week (standard drink is defined as a 12 oz beer, 5 oz glass of wine, or 1.5 oz of distilled spirit)
  • Positive urine drug screen for amphetamine, methamphetamine, cocaine, and opioids at screening.
  • Subjects who have donated more than 1500 mL (males) or 1000 mL (females) blood in the previous 12 months, including the maximum volume of blood (328 mL) to be taken in this study.
Show all 28Show fewer
  • Subjects who are currently enrolled in another study involving an investigational product, or if recently involved in another clinical trial which has ended, have not received any investigational products within the past 3 months or 5 half-lives (whichever is longer) from the time of screening.
  • Any history of malaria infection in the past 3 years.
  • History of travel to malaria endemic areas in the 3 months prior to day of challenge, or plans to travel to malaria endemic areas during the duration of the study (56 days post challenge).
  • Any history of receiving a malaria vaccine
  • History of receipt of malaria prophylaxis during the 2 months prior to day of challenge
  • History of use of any antibiotics with significant antimalarial activity (examples include tetracycline, doxycycline, clindamycin, azithromycin, and sulfa drugs) during the course of the study period
  • Pregnant (positive β-human chorionic gonadotropin test, β-HCG) or lactating female at screening or plans to become pregnant or breastfeed from the time of enrollment until three months after challenge
  • Allergy to antimalarial drugs or use of medications known to interact with CQ
  • Significant (e.g., systemic) hypersensitivity reactions to mosquito bites (local hypersensitivity reactions at the site of mosquito bites are not an exclusion criterion)
  • History of splenectomy
  • Any confirmed or suspected immunodeficiency, including HIV infection, or taking immunosuppressive medications
  • Acute or chronic, ally significant, pulmonary, cardiovascular, endocrine, hepatic, or renal functional abnormality, as determined by history, physical examination, or laboratory evaluation
  • Chronic or active neurologic disease including seizure disorder and chronic migraine headaches
  • Any abnormal baseline laboratory screening tests listed below
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) above twice the upper limit of normal for the reference lab
  • Creatinine above normal range
  • Hemoglobin out of normal range
  • Platelet count out of normal range
  • Total white blood cell (WBC) count out of normal range Note: If screening lab values are out of the normal range but are expected to be temporary (e.g. due to dehydration), they may be re-assessed one time at the discretion of the investigator.
  • Seropositive for Human immunodeficiency virus (HIV) or Hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) positive
  • An abnormal baseline screening ECG suggestive of cardiac disease as determined by a clinical investigator. QTcF of >450 msec for males and >470 msec for females.
  • Any other significant finding that in the opinion of the PI would increase the risk of having an adverse outcome from participating in this study

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Clinical Research Unit, Uniformed Services University of Health Sciences

    Bethesda, Maryland, 20814

  • WRAIR

    Silver Spring, Maryland, 20910

Other trials in United States

About this study

Official title: A Phase 2a Open Label Study of the Safety and Efficacy of a Single Dose of Weekly Chloroquine (CQ) and Azithromycin (AZ) Administered in Combination for Malaria Prophylaxis in Healthy Adults Challenged With 7G8 Chloroquine-Resistant Plasmodium Falciparum in a Controlled Human Malaria Infection (CHMI) Model

This is an open label, Phase 2 study with controlled human malaria infection (CHMI). Twenty three subjects will be enrolled into 2 groups (15 subjects in the Chloroquine-Azithromycin [CQ/AZ] Intervention Group, and 8 subjects in the Chloroquine [CQ] Group). The CQ/AZ Group will receive experimental intervention of 300 mg of CQ and 2 g of azithromycin (AZ). The CQ Group will receive 300 mg of CQ only. All subjects will participate in the CHMI and will be required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to all symptomatic parasitemic subjects under directly observed treatment.

Read the detailed description

This study is a Phase 2, open-label study of the combination of a single dose-level of AZ (Zithromax) plus CQ given weekly as a prophylaxis against CQ-resistant P falciparum in healthy adults. After signing informed consent, subjects will undergo screening procedures between Day -77 to Day -18. If enrolled, subjects who are still eligible at Study Day -18 will be randomized to either the CQ/AZ group (Group 1 of 15 subjects: 2 g AZ (Zithromax) plus 300 mg CQ base weekly for 6 weeks), or the CQ control group (Group 2 of 8 subjects: 300 mg chloroquine base weekly for 6 weeks) and start intervention on Study Day -17. The rationale for the CQ control group to receive CQ is to show that the strain utilized (7G8) is indeed chloroquine resistant in humans: we expect all of the subjects in the CQ control group to become symptomatically parasitemic. If 3 or more subjects in the CQ control group do not become symptomatic with malaria, the CHMI will be considered uncontrolled either due to 7G8 not being CQ-resistant, or the parasite not being infective.

Conditions
Malaria
Being tested
Chloroquine-Azithromycin (CQ/AZ), Chloroquine (CQ), atovaquone-proguanil (Malarone®)
Medical subject headings
Malaria

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Chloroquine-Azithromycin (CQ/AZ)Drug

    Also called CQ/AZ

    Chloroquine-Azithromycin (CQ/AZ); Chloroquine (CQ) 300mg and 2g of azithromycin (AZ) given orally

  • Chloroquine (CQ)Drug

    Also called CQ

    Chloroquine (CQ); 300 mg of CQ only given orally

  • atovaquone-proguanil (Malarone®)Drug

    All subjects will participate in the Controlled Human Malaria Infection (CHMI) and will be required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to all symptomatic parasitemic subjects under directly observed treatment.

Study groups in NCT03278808
Study groupRoleWhat they receive
Chloroquine-Azithromycin (CQ/AZ ) GroupExperimentalSubjects will receive experimental intervention of 300mg of CQ orally (PO) and 2g of AZ PO weekly for 6 weeks
Receives: Drug: Chloroquine-Azithromycin (CQ/AZ)
Chloroquine (CQ) GroupActive comparatorSubjects will only receive 300mg of CQ orally (PO) weekly for 6 weeks
Receives: Drug: Chloroquine (CQ)
CHMI Group - atovaquone-proguanil (Malarone®)OtherAll subjects will participate in the Controlled Human Malaria Infection (CHMI) and will be required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to all symptomatic parasitemic subjects under directly observed treatment.
Receives: Drug: atovaquone-proguanil (Malarone®)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Efficacy: Proportion of subjects free from symptomatic parasitemic subjects

    CQ/AZ Group will be compared to endpoint in CQ Group by Fisher's Exact Test. Symptomatic is defined as any one of the following solicited adverse events that first occurred concurrent with parasitemia: fever (temperature > 100.4 °F), chills, headache, arthralgia, myalgia, nausea, vomiting, or abdominal pain. Subjects will only undergo malaria treatment after both criteria are met.

    Measured: Days 1 thru 56

Secondary outcomes (6)

  1. Safety: Solicited and unsolicited Adverse Events in each group

    Groups will be analyzed by descriptive statistics and safety monitoring will be conducted throughout the study

    Measured: Days 1 thru 56

  2. Electrocardiogram baseline vs peak concentration for AZ

    QTcF will be analyzed for CQ/AZ Group subjects at presumed field-effective time point (Day 11 post challenge) 6 hours after dosing, which will coincide with time to peak concentration for AZ. This will be compared to baseline reading

    Measured: Day 11 post challenge, 6 hours after dosing

  3. Pharmacokinetics: Cmax - comparison for CQ/AZ-Group subjects

    Cmax will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.

    Measured: Days 11 thru 15

  4. Pharmacokinetics: Tmax - comparison for CQ/AZ-Group

    Tmax will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.

    Measured: Days 11 thru 15

  5. Pharmacokentics: T½ - comparison for CQ/AZ Group

    T½ will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group

    Measured: Days 11 thru 15

  6. Pharmacokentics: AUC - comparison for CQ/AZ Group

    Area under the curve (AUC) will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.

    Measured: Days 11 thru 15

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Sep 2017
  2. Study start17 Sep 2018
  3. Primary completion30 Dec 2019
  4. Study completion1 Jan 2020

Why it stopped: The IND has been withdrawn from FDA

Resources

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
Model description
Subjects will be randomized to either the CQ/AZ group (Group 1 of 15 subjects: 2 g AZ (Zithromax) plus 300 mg CQ base weekly for 6 weeks), or the CQ control group (Group 2 of 8 subjects: 300 mg chloroquine base weekly for 6 weeks)
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03278808
Sponsor's protocol ID
S-16-06
Status last verified
Feb 2020
First submitted
24 Aug 2017
Last updated
27 Feb 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Heppner DG Jr, Walsh DS, Uthaimongkol N, Tang DB, Tulyayon S, Permpanich B, Wimonwattrawatee T, Chuanak N, Laoboonchai A, Sookto P, Brewer TG, McDaniel P, Eamsila C, Yongvanitchit K, Uhl K, Kyle DE, Keep LW, Miller RE, Wongsrichanalai C. Randomized, controlled, double-blind trial of daily oral azithromycin in adults for the prophylaxis of Plasmodium vivax malaria in Western Thailand. Am J Trop Med Hyg. 2005 Nov;73(5):842-9.

    PubMed 16282291

  • Pereira MR, Henrich PP, Sidhu AB, Johnson D, Hardink J, Van Deusen J, Lin J, Gore K, O'Brien C, Wele M, Djimde A, Chandra R, Fidock DA. In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine. Antimicrob Agents Chemother. 2011 Jul;55(7):3115-24. doi: 10.1128/AAC.01566-10. Epub 2011 Apr 4.

    PubMed 21464242

  • Taylor WR, Richie TL, Fryauff DJ, Picarima H, Ohrt C, Tang D, Braitman D, Murphy GS, Widjaja H, Tjitra E, Ganjar A, Jones TR, Basri H, Berman J. Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in Irian Jaya, Indonesia. Clin Infect Dis. 1999 Jan;28(1):74-81. doi: 10.1086/515071.

    PubMed 10028075

  • Yeo AE, Rieckmann KH. Increased antimalarial activity of azithromycin during prolonged exposure of Plasmodium falciparum in vitro. Int J Parasitol. 1995 Apr;25(4):531-2. doi: 10.1016/0020-7519(94)00119-9.

    PubMed 7635629

  • Andersen SL, Oloo AJ, Gordon DM, Ragama OB, Aleman GM, Berman JD, Tang DB, Dunne MW, Shanks GD. Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin Infect Dis. 1998 Jan;26(1):146-50. doi: 10.1086/516281.

    PubMed 9455524

  • Biswas S. In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum. J Postgrad Med. 2001 Oct-Dec;47(4):240-3.

    PubMed 11832638

  • Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Dev V, Patel K, Mohapatra MK, Lakhani J, Benner R, Lele C, Patki K. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J Infect Dis. 2005 May 15;191(10):1582-8. doi: 10.1086/429343. Epub 2005 Apr 11.

    PubMed 15838784

  • Mzayek F, Deng H, Mather FJ, Wasilevich EC, Liu H, Hadi CM, Chansolme DH, Murphy HA, Melek BH, Tenaglia AN, Mushatt DM, Dreisbach AW, Lertora JJ, Krogstad DJ. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin Trials. 2007 Jan 5;2(1):e6. doi: 10.1371/journal.pctr.0020006.

    PubMed 17213921

  • Livezey J, Twomey P, Morrison M, Cicatelli S, Duncan EH, Hamer M, Lee C, Hutter J, Mills K, DeLuca J, Poon L, Selig D, Vuong C, Sousa J, Oliver T, Bennett J, Moon JE, Sikaffy A, Sedegah M, Tosh D, Kreishman-Deitrick M, Waterman P. An open label study of the safety and efficacy of a single dose of weekly chloroquine and azithromycin administered for malaria prophylaxis in healthy adults challenged with 7G8 chloroquine-resistant Plasmodium falciparum in a controlled human malaria infection model. Malar J. 2020 Sep 16;19(1):336. doi: 10.1186/s12936-020-03409-z.

    PubMed 32938444

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Chloroquine-Azithromycin (CQ/AZ), Chloroquine (CQ) and atovaquone-proguanil (Malarone®) in people with Malaria, run by U.S. Army Medical Research and Development Command at 2 sites in United States.

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 14 inclusion and 28 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: withdrawn, as of the sponsor's last update on 27 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. 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. 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 was withdrawn before enrolling participants, so there are no results.

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?

Efficacy: Proportion of subjects free from symptomatic parasitemic subjects (time frame: Days 1 thru 56). 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 NCT03278808, which also lists 9 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 27 Feb 2020.

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Clinical Trial NCT03278808 | AzTrials