Ignite Creation Date:
2024-05-05 @ 4:50 PM
Last Modification Date:
2024-10-26 @ 9:24 AM
Study NCT ID:
NCT00323375
Status:
COMPLETED
Last Update Posted:
2020-12-08
First Post:
2006-05-05
Brief Title:
Studies of AQ-13 a Candidate Aminoquinoline Antimalarial in Comparison With Chloroquine
Sponsor:
Tulane University Health Sciences Center
Organization:
Tulane University
Study Overview
Official Title:
Randomized Controlled Trial of AQ-13 a Candidate Aminoquinoline Antimalarial in Comparison With Chloroquine
Status:
COMPLETED
Status Verified Date:
2020-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this protocol is to perform Phase 1 safetytoxicity and pharmacokinetic Studies of an investigational aminoquinoline antimalarial AQ-13 in human subjects The compound to be studied AQ-13 is being examined because it is active in vitro against Plasmodium falciparum malaria parasites resistant to chloroquine CQ and other antimalarials multi-resistant P falciparum and because its safety was similar to that of CQ in preclinical studies performed by SRI International IND 55670 AQ-13 was also selected for study because it is active in vivo in two monkey models of human malaria 1 P cynomolgi in the rhesus monkey Macaca mulatta a model of human infection with P vivax and 2 CQ-resistant P falciparum in the squirrel monkey a model of human infection with CQ-resistant P falciparum
Detailed Description:
Study Population
Healthy young men and women 21-45 years of age who are taking no chronic medications with the exception of birth control pills will be invited to participate in this Phase 1 Study at the TulaneLSUCharity Hospital General Clinical Research Center GCRC in New Orleans Exclusion criteria include pregnancy breast feeding abnormal liver or kidney function tests anemia Hb 12 gm per dL chronic medications other than birth control pills and an abnormal baseline ECG or Holter recording Because the purpose of this testing is to determine whether AQ-13 is likely to have significant toxicity in Africans Malians 25 of the volunteers studied in New Orleans will be African-Americans
Randomization
Drug allocation codes will be generated by the study biostatistician in blocks of size 4 and 6 using computer software and will be sealed in numbered opaque envelops Block sizes will be determined at random so that they will not be known to the study personnel The envelopes containing the randomization codes will be hand-delivered to the study pharmacist and kept in the Research Pharmacy which is outside the GCRC
Blinding
The study participants investigators and staff will be blinded to the type of the drug administered throughout the study The interim reports to the DSMB after completion of each dose level will be presented without breaking the code unless deemed necessary by the DSMB The envelope containing the drug allocation code will be opened by the study pharmacist and the appropriate drug will be dispensed to the GCRC on the morning of its administration With the exception of the 600 mg CQ tablets Aralen tablets the two drugs AQ-13 and CQ will be administered in identical capsular form and number
Informed Consent
Informed consent will be obtained from each participant before screening As per the IRB regulations the informed consent form will be updated and reviewed at yearly intervals or whenever new pertinent information on the study drugs or their side effects becomes available
Baseline Screening
To determine their eligibility each volunteer will have a complete physical exam including an eye examination visual acuity visual fields indirect ophthalmoscopy panels of standard chemical tests BUN Creatinine AST ALT LDH Alkaline Phosphatase Glucose Bilirubin Creatine Kinase and hematologic tests Hematocrit Hemoglobin White Cell Count and Platelet Count and a cardiac examination physical exam baseline ECG and 24-hour Holter recording for arrhythmias and other evidence of cardiac disease
In-patient Studies at the Tulane-LSU-Charity Hospital GCRC
Volunteers will be hospitalized the night before drug administration at the GCRC prior to randomization to receive either AQ-13 or CQ capsules orally po the next morning Doses will begin at 10 mg base with 8 volunteers per drug x dose group and will escalate in subsequent groups to 100 300 and 600 mg base 8 subjects per drug x dose group for the 10 100 and 300 mg doses subtotal of 48 subjects 12 subjects per drug x dose group at the 600 mg dose in order to compare the pharmacokinetics of CQ and AQ-13 before proceeding to the equivalent therapeutic dose At the request of FDA a third group will be added at the 600 mg dose to determine whether the blood levels obtained with CQ capsules are equivalent to the blood levels obtained with commercially available FDA-approved Sanofi-Winthrop CQ tablets Aralen ie 12 subjects per drug x dose group at 600 mg x 3 drug groups AQ-13 capsules CQ capsules and Aralen CQ tablets subtotal of 36 subjects
To compare the absorption and metabolism of AQ-13 with the absorption and metabolism of CQ blood samples will be obtained for AQ-13 CQ and metabolite blood levels immediately before and 1 2 4 6 8 12 18 24 36 48 60 72 84 96 and 120 hours after the 600 and the 1500 mg doses using a heparin lock At the 1500 mg dose three 24-hour urine collections will be obtained on days 1-3 after beginning dosing on day 1 to compare the urinary excretion of AQ-13 CQ and their metabolites Volunteers receiving 600 and 1500 mg doses of AQ-13 or CQ will return for blood samples twice weekly during the ensuing 4 weeks to define the terminal half-lives of AQ-13 CQ and their metabolites After measurement of AQ-13 CQ and metabolite levels following the 600 mg dose the doses given in the second set of studies equivalent therapeutic course - ie 1500 mg CQ will be adjusted Dose Adjustment see below to obtain blood levels of AQ-13 similar to those obtained with CQ In these studies volunteers will receive the equivalent of 600 mg CQ base on the mornings of days 1 and 2 and an additional 300 mg CQ base equivalent on day 3
Previous experience with CQ a structurally similar aminoquinoline suggests that massive overdoses of AQ-13 may produce arrhythmias although there has been no previous human experience with AQ-13 Although the arrhythmiagenic effects of CQ have been reported only with massive ingestions or rapid intravenous infusions these Phase 1 Studies will provide an excellent opportunity to test for this potential toxicity Therefore investigators will use Holter monitoring during the Phase 1 Studies in New Orleans to ensure that there is no evidence of arrhythmias with AQ-13 Conventional electrocardiograms will be used to test for the T wave flattening and QTc prolongation typically seen in persons receiving therapeutic courses of CQ Continuous Holter monitoring will be performed to evaluate the effects of AQ-13 and CQ on the QT interval after the 1500 mg dose
Participants Out-patient Follow-ups
After discharge from their in-patient stay at the GCRC 2½ days for the 10 100 300 and 600 mg doses 3½ days for the 1500 mg dose participants will be asked to return to the GCRC twice weekly for a total of 4 weeks after discharge in order to obtain blood for drug and metabolite blood levels and for the evaluation of adverse events AEs An ECG and chemistry and hematology lab tests will be repeated at the 2 week and 4 week follow-up visits
Dose Adjustment for AQ-13
The data obtained by SRI International during GLP preclinical toxicologic and pharmacokinetic studies indicate that the oral bioavailability of AQ-13 is less than that of CQ in rats and monkeys Therefore it is possible perhaps likely that the oral bioavailability of AQ-13 in humans will be less than that of CQ and thus that it may be necessary to increase the oral dose of AQ-13 in order to provide molar blood levels of AQ-13 similar to those produced by the established oral doses of CQ To estimate the amount of AQ-13 necessary to obtain similar oral bioavailability investigators will compare blood levels and areas under the curve AUCs for AQ-13 and CQ at the 600 mg dose Based on these results researchers will estimate the dose adjustment increment or decrement necessary for AQ-13 and test that adjustment in 12 additional volunteers After the dose of AQ-13 necessary to produce equimolar blood levels and AUCs has been established investigators will compare that adjusted dose to 1500 mg CQ base for the equivalent therapeutic dose of AQ-13
Healthy young men and women 21-45 years of age who are taking no chronic medications with the exception of birth control pills will be invited to participate in this Phase 1 Study at the TulaneLSUCharity Hospital General Clinical Research Center GCRC in New Orleans Exclusion criteria include pregnancy breast feeding abnormal liver or kidney function tests anemia Hb 12 gm per dL chronic medications other than birth control pills and an abnormal baseline ECG or Holter recording Because the purpose of this testing is to determine whether AQ-13 is likely to have significant toxicity in Africans Malians 25 of the volunteers studied in New Orleans will be African-Americans
Randomization
Drug allocation codes will be generated by the study biostatistician in blocks of size 4 and 6 using computer software and will be sealed in numbered opaque envelops Block sizes will be determined at random so that they will not be known to the study personnel The envelopes containing the randomization codes will be hand-delivered to the study pharmacist and kept in the Research Pharmacy which is outside the GCRC
Blinding
The study participants investigators and staff will be blinded to the type of the drug administered throughout the study The interim reports to the DSMB after completion of each dose level will be presented without breaking the code unless deemed necessary by the DSMB The envelope containing the drug allocation code will be opened by the study pharmacist and the appropriate drug will be dispensed to the GCRC on the morning of its administration With the exception of the 600 mg CQ tablets Aralen tablets the two drugs AQ-13 and CQ will be administered in identical capsular form and number
Informed Consent
Informed consent will be obtained from each participant before screening As per the IRB regulations the informed consent form will be updated and reviewed at yearly intervals or whenever new pertinent information on the study drugs or their side effects becomes available
Baseline Screening
To determine their eligibility each volunteer will have a complete physical exam including an eye examination visual acuity visual fields indirect ophthalmoscopy panels of standard chemical tests BUN Creatinine AST ALT LDH Alkaline Phosphatase Glucose Bilirubin Creatine Kinase and hematologic tests Hematocrit Hemoglobin White Cell Count and Platelet Count and a cardiac examination physical exam baseline ECG and 24-hour Holter recording for arrhythmias and other evidence of cardiac disease
In-patient Studies at the Tulane-LSU-Charity Hospital GCRC
Volunteers will be hospitalized the night before drug administration at the GCRC prior to randomization to receive either AQ-13 or CQ capsules orally po the next morning Doses will begin at 10 mg base with 8 volunteers per drug x dose group and will escalate in subsequent groups to 100 300 and 600 mg base 8 subjects per drug x dose group for the 10 100 and 300 mg doses subtotal of 48 subjects 12 subjects per drug x dose group at the 600 mg dose in order to compare the pharmacokinetics of CQ and AQ-13 before proceeding to the equivalent therapeutic dose At the request of FDA a third group will be added at the 600 mg dose to determine whether the blood levels obtained with CQ capsules are equivalent to the blood levels obtained with commercially available FDA-approved Sanofi-Winthrop CQ tablets Aralen ie 12 subjects per drug x dose group at 600 mg x 3 drug groups AQ-13 capsules CQ capsules and Aralen CQ tablets subtotal of 36 subjects
To compare the absorption and metabolism of AQ-13 with the absorption and metabolism of CQ blood samples will be obtained for AQ-13 CQ and metabolite blood levels immediately before and 1 2 4 6 8 12 18 24 36 48 60 72 84 96 and 120 hours after the 600 and the 1500 mg doses using a heparin lock At the 1500 mg dose three 24-hour urine collections will be obtained on days 1-3 after beginning dosing on day 1 to compare the urinary excretion of AQ-13 CQ and their metabolites Volunteers receiving 600 and 1500 mg doses of AQ-13 or CQ will return for blood samples twice weekly during the ensuing 4 weeks to define the terminal half-lives of AQ-13 CQ and their metabolites After measurement of AQ-13 CQ and metabolite levels following the 600 mg dose the doses given in the second set of studies equivalent therapeutic course - ie 1500 mg CQ will be adjusted Dose Adjustment see below to obtain blood levels of AQ-13 similar to those obtained with CQ In these studies volunteers will receive the equivalent of 600 mg CQ base on the mornings of days 1 and 2 and an additional 300 mg CQ base equivalent on day 3
Previous experience with CQ a structurally similar aminoquinoline suggests that massive overdoses of AQ-13 may produce arrhythmias although there has been no previous human experience with AQ-13 Although the arrhythmiagenic effects of CQ have been reported only with massive ingestions or rapid intravenous infusions these Phase 1 Studies will provide an excellent opportunity to test for this potential toxicity Therefore investigators will use Holter monitoring during the Phase 1 Studies in New Orleans to ensure that there is no evidence of arrhythmias with AQ-13 Conventional electrocardiograms will be used to test for the T wave flattening and QTc prolongation typically seen in persons receiving therapeutic courses of CQ Continuous Holter monitoring will be performed to evaluate the effects of AQ-13 and CQ on the QT interval after the 1500 mg dose
Participants Out-patient Follow-ups
After discharge from their in-patient stay at the GCRC 2½ days for the 10 100 300 and 600 mg doses 3½ days for the 1500 mg dose participants will be asked to return to the GCRC twice weekly for a total of 4 weeks after discharge in order to obtain blood for drug and metabolite blood levels and for the evaluation of adverse events AEs An ECG and chemistry and hematology lab tests will be repeated at the 2 week and 4 week follow-up visits
Dose Adjustment for AQ-13
The data obtained by SRI International during GLP preclinical toxicologic and pharmacokinetic studies indicate that the oral bioavailability of AQ-13 is less than that of CQ in rats and monkeys Therefore it is possible perhaps likely that the oral bioavailability of AQ-13 in humans will be less than that of CQ and thus that it may be necessary to increase the oral dose of AQ-13 in order to provide molar blood levels of AQ-13 similar to those produced by the established oral doses of CQ To estimate the amount of AQ-13 necessary to obtain similar oral bioavailability investigators will compare blood levels and areas under the curve AUCs for AQ-13 and CQ at the 600 mg dose Based on these results researchers will estimate the dose adjustment increment or decrement necessary for AQ-13 and test that adjustment in 12 additional volunteers After the dose of AQ-13 necessary to produce equimolar blood levels and AUCs has been established investigators will compare that adjusted dose to 1500 mg CQ base for the equivalent therapeutic dose of AQ-13
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01AI025136 | NIH | Centers for Disease Control | httpsreporternihgovquickSearchR01AI025136 |
| FDA Phase 1 FD R01-001692 | OTHER_GRANT | None | None |
| UR3CCU 418652 | OTHER_GRANT | None | None |
| U01CI000211 | NIH | None | None |