1. Medicine
  2. Microbiology and Infectious Disease
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An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis

  1. Nguyen Thi Thuy Ngan
  2. Nhat Thanh Hoang Le
  3. Nguyen Ngo Vi Vi
  4. Ninh Thi Thanh Van
  5. Nguyen Thi Hoang Mai
  6. Duong Van Anh
  7. Phan Hai Trieu
  8. Nguyen Phu Huong Lan
  9. Nguyen Hoan Phu
  10. Nguyen Van Vinh Chau
  11. David G Lalloo
  12. William Hope
  13. Justin Beardsley
  14. Nicholas J White
  15. Ronald Geskus
  16. Guy E Thwaites
  17. Damian Krysan
  18. Luong Thi Hue Tai
  19. Evelyne Kestelyn
  20. Tran Quang Binh
  21. Le Quoc Hung
  22. Nguyen Le Nhu Tung
  23. Jeremy N Day  Is a corresponding author
  1. Department of Tropical Medicine, Cho Ray Hospital, Viet Nam
  2. Oxford University Clinical Research Unit, Viet Nam
  3. The Hospital for Tropical Diseases, Viet Nam
  4. Liverpool School of Tropical Medicine, United Kingdom
  5. Centre of Excellence in Infectious Disease Research, Institute of Translational Medicine, Liverpool University, United Kingdom
  6. The University of Sydney, Marie Bashir Institute, NSW, Australia
  7. Westmead Institute for Medical Research, Australia
  8. Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Thailand
  9. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom
  10. Department of Paediatrics and Microbiology/Immunology, Carver College of Medicine, University of Iowa, United States
Research Article
Cite this article as: eLife 2021;10:e68929 doi: 10.7554/eLife.68929
4 figures, 4 tables and 1 additional file

Figures

Trial flow chart: enrollment, randomization, and follow-up.
The impact of addition of tamoxifen to standard treatment on (A) the rate of sterilzation of cerebrospinal fluid, and (B) survival until 10 weeks after randomisation.

(A) Decline in fungal count in CSF as measured in colony-forming units (CFU) per milliliter over the first 2 weeks of treatment by treatment arm. Data from individual patients are shown in grey lines. Bold blue lines show estimated mean with 95% credible intervals (shaded band) of CSF fungal counts based on the joint model described in the statistical analysis. The rate of decline was −0.49 log10CFU/ml/day in patients receiving tamoxifen versus −0.48 log10CFU/ml/day in control patients. The horizontal dashed lines represent the value of detection limit (4.5 CFU/ml). The fitted line crosses the horizontal dashed lines of the detection limit value after day 8 because 25% and 75% of patients had fungal counts under the detection limit at days 8 and 15, respectively. (B) Kaplan-Meier survival cures for each study arm over the 10-week study period. Seven death events occurred in the control arm versus 8 in the tamoxifen intervention arm by 10 weeks (estimated risk 27% versus 34%, absolute risk difference = 6.5%) (95% Confidence Interval −19.2 to 32.1%, p = 0.62).

Change in QTc interval over the first 2 weeks of treatment by study arm.

Faint lines display change in individual patient QTcs; bold lines display the estimated mean and shaded bands the 95% Confidence Intervals; blue = control arm, red = tamoxifen arm. The maximum median difference in the QTc intervals between study arms immediately prior to drug administration was 37.07 ms (95% CI: 21.09, 53.04) and occurred on day 9 of the study. The largest difference in median QTc 2 hr post-drug administration was 33.44 ms (95% CI: 18.67, 48.21) and occurred on day 8 of the study. Additional details regarding change in QTc are provided in the Supplementary Appendix.

Appendix 1—figure 1
Graphical representation of differences in QTc between study arm of ther first 2 weeks of the trial.

The bold lines and the shaded bands represent the estimated mean difference with 95% Confidence Interval of QTc between two study arms. The output of the fitted linear mixed effect model computes the differences in QTc between study arms by study day, separately for pre-dose and 2 hours post-dose measurements.

Tables

Table 1
Clinical and investigation characteristics of patients at study entry.
CharacteristicTotalTamoxifenTotalControl
NN (%) or IQR*NN (%) or IQR*
Male sex2417 (71)2618 (69)
Median age in years2435
(31, 39)
2632
(25, 35)
History of intravenous drug use243 (13)263/26 (12)
HIV infection2419 (83)2621/26 (81)
Current antiretroviral-therapy use
None2418 (75)2622 (84)
≤3 months duration244 (17)262 (8)
>3 months duration242 (8)262 (8)
Median duration of illness — days2414
(10, 25)
2612
(7, 28)
Symptoms
Headache2424 (100)2626 (100)
Fever2422 (92)2623 (88)
Neck stiffness2220 (91)2621 (81)
Seizures242 (8)263 (12)
Abnormal visual acuity226 (27)264 (15)
Papilledema212 (10)251 (4)
Glasgow Coma Scale score2426
1519 (79)24 (92)
11–145 (21)2 (8)
<110 (0)0 (0)
Cranial nerve palsy
None2419 (79)2623 (88)
Cranial nerve VI244 (17)261 (4)
Other cranial nerve241 (4)263 (11)
Investigations
Median CSF opening pressure — cm of CSF1926.5
(18, 37)
2324.5
(16, 47)
Median CSF white-cell count in HIV infected patients — cells/mm31838.5
(7, 52)
2027
(10, 55)
Median CSF white-cell count in HIV uninfected patients — cells/mm35122
(64, 187)
594
(45, 117)
Median CSF glucose — mmol/l242.47
(1.70, 3.14)
252.31
(1.44, 2.76)
Median blood glucose — mmol/l245.86
(4.92, 6.84)
266.21
(5.11, 7.81)
Median CSF: blood glucose ratio240.40
(0.24, 0.53)
250.37
(0.16, 0.45)
Median CSF fungal count — log10 CFU/ml244.60
(3.90, 5.17)
265.16
(3.17, 5.87)
Median CD4 count in HIV infected patients — cells/mm31720
(8, 49)
2117
(9, 45)
Median CD4 count in HIV uninfected patients — cells/mm35376
(348, 382)
5504
(305, 968)
Median creatinine — mg/dl240.82
(0.66, 1.05)
260.78
(0.66, 0.98)
QTc interval — ms24395.03
(377.55, 410.45)
26401.20
(374.76, 420.06)
  1. * Median, interquartile range (IQR) for continuous data and N (%) for categorical data.

Table 2
Primary outcome: Early Fungicidal Activity over the first 2 weeks following randomization (log10 colony-forming units (CFU)/ml/day).
Treatment Arm
Analysis populationsTotalTamoxifenTotalStandard of CareDifference in changep-value
NChange/day (95% CI*)NChange/day (95% CI*)(95% CI*)
Intention-to-treat24−0.49
(−0.62,–0.37)
26−0.48
(−0.61,–0.37)
−0.005
(−0.16, 0.15)
0.95
Per-protocol23−0.48
(−0.61,–0.36)
25−0.48
(−0.61,–0.37)
0.004
(−0.17, 0.17)
0.96
HIV-infected patients19−0.49
(−0.65,–0.37)
21−0.42
(−0.55,–0.31)
−0.072
(−0.25, 0.10)
0.41
HIV-uninfected patients5−0.42
(−0.74,–0.21)
5−0.57
(−0.93,–0.33)
0.16
(−0.18, 0.55)
0.37
  1. *95% CI corresponds to Bayesian 95% credible intervals.

    p-value refers to crude ‘Wald-type’ tests of the mean estimate divided by its standard deviation of the Monte Carlo Markov chain sampling of coefficients derived from the joint model.

Table 3
Secondary outcomes: death, disability, and change in CD4 count.
Death by 10 weeksTamoxifen
N/total (%)
Control
N/total (%)
Risk difference
% (95% CI)
p- value*
Intention-to-treat population8/24 (34)7/26 (27)6.47
(−19.15, 32.09)
0.62
Per-protocol population7/23 (31)6/25 (24)6.50
(−18.90, 31.89)
0.62
HIV infected patients7/19 (37)6/21 (29)8.39
(−20.99, 37.77)
0.58
HIV uninfected patients1/5 (20)1/5 (20)0.00
(−49.58, 49.58)
1.00
Disability at 10 weeks0.14
Good2/23 (9)9/25 (36)
Intermediate7/23 (30)6/25 (24)
Severe disability6/23 (26)3/25 (12)
Death8/23 (35)7/25 (28)
Disability at 10 weeks in HIV infected patients0.05
Good2/18 (11)8/20 (40)
Intermediate5/18 (28)6/20 (30)
Severe disability4/18 (22)0/20 (0)
Death7/18 (39)6/20 (30)
Disability at 10 weeks in HIV uninfected patients0.68
Good0/5 (0)1/5 (20)
Intermediate2/5 (40)0/5 (0)
Severe disability2/5 (40)3/5 (60)
Death1/5 (20)1/5 (20)
Change in CD4 count over 10 weeks (cells/uL)Median Change (IQR)
(N)
Median Change (IQR)
(N)
HIV-infected patients50.0
(5.00, 142.5)
(10)
40.0
(7.0, 76.0)
(13)
0.5
HIV-uninfected patients393.5
(211.3, 613.8)
(4)
−257.5
(−413.7,–171.0)
(4)
0.02
  1. *p-Values not corrected for multiple testing.

Table 4
Grade 3 or 4 adverse events by 10 weeks.
EventTamoxifen (N = 24)Control (N = 26)p-value*
Number of patients with Grade 3 or 4 adverse events (%)
Any adverse event24 (100)26 (100)1.0
New neurological events9 (38)7 (27)0.62
New AIDS-defining illness (HIV patients only)3 (16)5 (24)0.58
New cardiac events9 (38)4 (15)0.145
Supraventricular tachycardia1 (4)0 (0)0.48
Ventricular extrasystoles3 (13)0 (0)0.21
Right Bundle Branch Block0 (0)1 (4)1.00
QTc prolongation8 (33)1 (4)0.02
Myocardial infarction0 (0)1 (4)1.00
Cardiac arrest1 (4)0 (0)0.48
Other cardiac adverse events1 (4)1 (4)1.0
Laboratory abnormalities
Anemia18 (75)18 (69)0.89
Leukopenia2 (8)2 (8)1.0
Thrombocytopenia2 (8)4 (15)0.74
Elevated aminotransferase2 (8)4 (15)0.74
Raised Creatinine3 (13)6 (23)0.55
Hyperkalemia2 (8)6 (23)0.48
Hypokalemia17 (71)20 (77)0.87
Hyponatremia18 (75)23 (88)0.39
  1. *p-Values were not corrected for multiple testing.

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