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. 2020 May 12;108(2):201–211. doi: 10.1002/cpt.1857

Table 4.

Summary of azithromycin and chloroquine combination studies

Study code and study title Age range of treated subjects Dose regimen (Number tested) Safety summary
A0661139: A multiple‐dose study to assess the effects of AZ + CQ on electrocardiograms in healthy subjects Adults, age 18–55 years
Five treatment groups; each treatment administered for 3 days:
  1. 600 mg a CQ (N = 24)
  2. 600 mg CQ + 500 mg AZ (N = 24)
  3. 600 mg CQ + 1,000 mg AZ (N = 24)
  4. 600 mg CQ + 1,500 mg AZ (N = 23)
  5. placebo (N = 24)

Most AEs were mild or moderate; no SAEs were reported which were considered related to study drug. Three subjects in the 1,500 mg AZ + CQ group discontinued due to AEs (diarrhea; loss of appetite; nausea, diarrhea, and vomiting). AE rates were similar across the combination treatment groups, although events of diarrhea, nausea, and vomiting were greater in the higher dose groups.

The primary end point was change from baseline in triplicate ECG measurements at each of 10 timepoints post dose on Day 3 vs. time‐matched triplicate ECGs on study Day −1 (baseline). Maximum mean increases in QTcF vs. placebo of approximately 35–37 msec were similar among all AZ + CQ and CQ alone treatments. In comparison with CQ alone, the maximum mean (90% CI) increases in QTcF were approximately 5.3 (0.2, 10.4) msec, 6.5 (1.4, 11.6) msec and 8.9 (3.6, 14.2) msec for the 500 mg, 1,000 mg and 1,500 mg AZ + CQ groups, respectively. Mean changes from time‐matched baseline QTcF (compared with placebo alone) ranged from 18.4 msec to 35.0 msec in the CQ alone group; 21.5 msec to 36.2 msec in the 500 mg AZ + CQ group; 19.9 msec to 36.9 msec in the 1,000 mg AZ + CQ group; and from 20.2 msec to 35.3 msec in the 1,500 mg AZ + CQ treatment group.
066‐191: a randomized, double blind, comparative study of AZ vs. CQ as treatment of Plasmodium falciparum and Plasmodium vivax malaria Adults, age 18–60 years (AZ) and 18–45 years (CQ)
Two treatment groups:
  1. 1,000 mg AZ; once daily for 3 days (N = 16)
  2. 600 mg CQ once daily on Days 1 and 2, then 300 mg CQ on Day 3 (N = 16) (due to poor activity of either agent alone against P. falciparum, study was modified to 066‐191B)

Two subjects treated for P. vivax were discontinued from the study due to AEs related to CQ (maculopapular rash (moderate), pruritus (severe))

There was one treatment‐related SAE of urticaria in the AZ treatment group.
066‐191B: A randomized, double blind, comparative study of AZ vs. CQ as treatment of P. falciparum and P. vivax malaria Adults, age 18–55 years 1,000 mg AZ + CQ (600 mg days 1 and 2, and 300 mg on day 3), for 3 days (N = 64)

There were no SAEs following treatment with AZ + CQ, and no discontinuations due to AEs.

Treatment with AZ + CQ was better tolerated than monotherapy with AZ or CQ alone in subjects with P. falciparum malaria
A0661120: A phase II/III, randomized, comparative trial of AZ plus CQ vs. SP plus CQ for the treatment of uncomplicated P. falciparum malaria in India Adults, age 18–75 years (AZ + CQ) and 18–60 years (SP + CQ)
Three treatment groups:
  1. 1,000 mg AZ + 600 mg CQ; once daily, for 3 days (N = 83)
  2. 500 mg AZ + 600 mg CQ; once daily, for 3 days (N = 67)
  3. 1,500 mg/75 mg SP on Day 0, 600 mg CQ on Days 0 and 1, and 300 mg on Day 2 (N = 80)
 Fewer than 10% subjects in all three groups reported treatment‐related AEs, and no subjects discontinued the study due to AEs related to study drug. One subject reported a treatment‐related SAE (“abnormal behaviour”) in the SP + CQ group which was attributed to CQ. All treatment‐related AEs occurred at an incidence of < 5% (≤ 4) subjects (vomiting, diarrhea, abdominal pain, pruritis, and gastritis) and all were mild or moderate. In the 500 mg AZ + CQ group, one (1.5%) subject reported vomiting and one (1.5%) subject reported pruritus. In the 1,000 mg AZ + CQ group, vomiting was reported by four (4.8%) subjects and pruritus was reported by two (2.4%) subjects. In addition, two (2.4%) subjects reported abdominal pain, and diarrhea and gastritis were reported by one (1.2%) subject each.
A0661126: A phase II/III, randomized, double blind, comparative trial of AZ plus CQ vs. A‐P for the treatment of uncomplicated P. falciparum malaria in South America Adults, aged 18–86 years (AZ + CQ) and 18–74 years (A‐P)
Three treatment groups; each treatment administered for 3 days:
  1. 1,000 mg AZ + 600 mg CQ (N = 114)
  2. 500 mg AZ + 600 mg CQ (N = 14) b
  3. 1,000 mg A + 400 mg P (A‐P) (N = 116)
 One subject in the 1000 mg AZ + CQ treatment group discontinued due to a treatment‐related AE of vomiting. The treatment‐related AEs most frequently reported by subjects treated with 500 mg AZ + CQ were pruritus (4 subjects; 28.6%), gastritis (1 subject (7.1%)) and mouth ulceration (1 subject (7.1%)); and with 1,000 mg AZ + CQ were pruritus (28 subjects; 24.6%), diarrhea/loose stools (8 subjects (7.1%)), and paresthesia (6 subjects (5.3%)). Most events were mild to moderate; three treatment‐related AEs were assessed as severe: pruritus (1,000 mg AZ + CQ), gastritis (500 mg AZ + CQ), and abdominal pain (A‐P). There were no treatment‐related SAEs. The incidence of AEs was higher in the AZ combination treatment groups than in the A‐P group and was attributed primarily to the incidence of pruritus which is secondary to CQ treatment.
A0661134: A phase II/III, randomized, double‐blind, comparative trial of AZ plus CQ vs. mefloquine for the treatment of uncomplicated P. falciparum malaria in Africa Adults, aged 18–63 years (AZ + CQ) and 18–68 years (mefloquine)
Three treatment groups:
  1. 1,000 mg AZ + 600 mg CQ, once daily for 3 days (N = 114)
  2. 500 mg AZ + 600 mg CQ, once daily for 3 days (N = 9) b
  3. 750 + 500 mg mefloquine on Day 0 (N = 115)
 Most frequently reported treatment‐related AEs with 500 mg AZ + CQ were pruritus (2 subjects (22.2%)), abdominal pain (1 subject (11.1%)), dyspepsia (1 subject (11.1%)), loose stools (1 subject (11.1%)), and vomiting (1 subject (11.1%)); and with 1,000 mg AZ + CQ were pruritus (58 subjects (50.9%)), vomiting (18 subjects (15.8%)), and headache (15 subjects (13.2%)); the majority of AEs were mild. There was one severe treatment‐related AE of vomiting in the 1,000 mg AZ + CQ treatment group, and two subjects from this treatment group discontinued the study due to vomiting and vomiting/dizziness/tinnitus. There were no SAEs which were considered related to AZ + CQ.
A0661154: A phase II, open label, noncomparative trial of AZ 2,000 mg plus CQ 600 mg base daily for three days for the treatment of uncomplicated P. falciparum malaria Adults, aged 18–77 years 2,000 mg AZ + 600 mg CQ (N = 110), each administered for 3 days

Most frequently reported treatment‐related AEs were nausea (30.0%), vomiting (18.2%), and diarrhea (11.8%) which were all mild or moderate with the exception of one severe event of vomiting. There were no SAEs or discontinuations due to AEs.

Triplicate ECGs were measured on Days 0 (predose), Days 1 and 2 (predose and postdose) and on Days 3 and 7. Mean increases in QTcF from baseline ranged from 12 msec to 49.9 msec and overall, 30 (29%), 6 (6%), and 2 (2%) subjects met the criteria of absolute QTcF values of 450 to < 480 msec, 480 to < 500 msec, and ≥ 500 msec, respectively. The QTcF prolongation observed was consistent with that reported for CQ alone and for AZ + CQ in previous studies. Coadministration of AZ did not worsen the QT prolongation associated with CQ.
A0661155: A phase III, randomized, open‐label, comparative trial of AZ plus CQ vs. mefloquine for the treatment of uncomplicated P. falciparum malaria in Africa Adults, aged 17–58 years (AZ + CQ) and 18 to 71 years (mefloquine)
Two treatment groups:
  1. 1,000 mg AZ + 600 mg CQ (N = 113), once daily for 3 days
  2. 750 + 500 mg mefloquine (N = 116)
 There were no SAEs in the AZ + CQ treatment group and all AEs in the AZ + CQ group were mild or moderate. One subject in this group discontinued due to an AE of pruritus. The most frequently reported treatment‐related AEs in the AZ + CQ group were pruritus (28.3%), headache (17.7%), dizziness (15.9%), abdominal pain (11.5%), nausea (8.8%), and vomiting (3.5%).
A0661157: phase II/III, open‐label, comparative trial of AZ plus CQ vs. AL for the treatment of uncomplicated P. falciparum malaria in children in Africa Children, aged 6 months to 12 years (both treatment groups)
Two treatment groups, each treatment administered for 3 days:
  1. AZCQ fixed‐dose combination tablet c (N = 179)
  2. AL 20 mg/120 mg (N = 182)

There were no SAEs considered to be related to study treatment and no permanent discontinuations from the study due to AEs; subjects discontinued from dosing more frequently in the AZCQ group, mostly due to vomiting. Most AEs were mild or moderate.

Vomiting and pruritus were more frequently reported in the AZCQ cohorts than the AL cohorts. The most frequently reported treatment‐related AEs (≥5%) in the AZCQ cohorts were vomiting, abdominal pain, parasitemia, malaria, pyrexia, and pruritus.

The QTc changes observed in this study were similar to those reported in African children with uncomplicated malaria treated with AL, SP, or CQ. The only AE reported was one of mild QT prolongation in a subject treated with AL, who had concurrent pyrexia.
A0661158: phase III, open‐label, randomized, comparative study to evaluate AZ plus CQ, and sulfadoxine plus pyrimethamine combinations for intermittent preventive treatment of falciparum malaria infection in pregnant women in Africa Pregnant subjects, aged 16–35 years (both treatment groups)
Two treatment groups:
  1. 1,000 mg/620 mg AZCQ (4× fixed‐dose combination tablet d ), for 3 treatment days (N = 1446)
  2. 1500 mg/75 mg SP (3× 500 mg/25 mg tablets on Day 0) (N = 1445)

Maternal group

There were three (0.2%) deaths in the AZCQ group and one (0.1%) in the SP group, but none were considered related to study drug. Most treatment‐related AEs were mild or moderate; 0.9% in the AZCQ group were considered severe. Five (0.3%) subjects had SAEs which were considered related to AZCQ (vomiting (three), dizziness (two), diarrhea and asthenia (one each)). The most common treatment‐related AEs in the AZCQ group were vomiting (44.6%), dizziness (31.4%), headache (15.3%), asthenia (15.2%), diarrhea (14.2%), nausea (14.2%), and blurred vision (10.0%).

Neonatal group

There were 25 (2.2%) neonatal deaths in the AZCQ group and 22 (1.8%) in the SP group, but no deaths were considered related to study drug. There were no SAEs considered related to study drug. Treatment‐related AEs in neonates exposed in utero to AZCQ were low birth weight baby (0.2%), anemia (0.1%), and jaundice neonatal (0.1%).
A0661201: An open label, noncomparative study to evaluate parasitological clearance rates and pharmacokinetics of AZ and CQ following administration of a fixed dose combination of AZCQ in asymptomatic pregnant women with P. falciparum parasitemia in sub‐Saharan Africa Pregnant subjects, aged 16–34 years 1,000 mg/620 mg AZCQ fixed‐dose combination tablet d , for 3 treatment days (N = 168)

Maternal group

No deaths occurred in the maternal group. The most common treatment‐related AEs occurring in ≥ 5 subjects were vomiting (20.2% subjects), dizziness (19.6% subjects), pruritus (7.1% subjects), headache and generalized pruritus (5.4% subjects each), fatigue (4.2% subjects), and nausea (3.6% subjects). All maternal TEAEs were mild or moderate. No SAEs were reported which were related to study drug and no AEs leading to discontinuations from the study.

Neonatal group

No treatment‐related AEs were reported for the neonatal group. There were four deaths, none of which were considered related to study drug. No SAEs were reported which were related to study drug.

AE, adverse event; AL, artemether‐lumefantrine; A‐P, atovaquone + proguanil; AZ, azithromycin; AZCQ, fixed‐dose combination of azithromycin and chloroquine; CQ, chloroquine; ECG, electrocardiogram; QTcF, corrected QT interval by Fridericia; SP, sulfadoxine‐pyrimethamine; SAE, serious adverse event; TEAE, treatment‐emergent adverse event.

a

For all CQ treatment administered in the studies in this table, CQ is noted as base amounts; e.g., 600 mg CQ base derived is from 1,000 mg CQ.

b

Treatment arm discontinued due to high failure rate of that arm.

c

AZCQ fixed dose combination: 300 mg AZ and 100 mg CQ, or 150 mg AZ and 50 mg CQ; tablets scored to allow for dosing by body weight.

d

AZCQ fixed dose combination tablet: 250 mg AZ and 155 mg CQ.