Recombinant human thrombopoietin (rhTPO) of different dosing regimens for refractory/relapsed primary immune thrombocytopenia: a multicenter, randomized controlled trial and pharmacokinetics study

Figures & data

Figure 1. The study flowchart. The full analysis set (FAS) included all patients who underwent randomization, received at least one dose of rhTPO, and had a baseline assessment and at least one post-baseline assessment. The per protocol set (PPS) included patients who met the eligibility criteria and completed the treatment as specified by the trial protocol and completed efficacy evaluation on day 14. The safety set included all patients who received at least one dose of rhTPO and had at least one follow-up safety assessment and was analyzed mainly using descriptive statistics. rhTPO, recombinant human thrombopoietin.

Table I. Patient demographic and baseline characteristics-the full analysis set (FAS).

Variables	7500-U QD (N = 64)	15000-U QD (N = 76)	15000-U QOD (N = 70)	30000-U QOD (N = 72)
Age, years
Mean(SD)	48·1(17·4)	47·6(16·5)	46·9(16·7)	46·7(18·6)
Range	18, 85	18, 82	21, 83	18, 90
Male sex	12(18·8%)	21(27·6%)	26(37·1%)	23(31·9%)
Ethnicity
Han Chinese	61(95·3%)	72(94·7%)	66(94·3%)	69(95·8%)
Others	3(4·7%)	4(5·3%)	4(5·7%)	3(4·2%)
Height, cm
Mean(SD)	161·6(7·4)	162·9(8·4)	163·7(8·3)	164·0(8·0)
Range	42·0, 110·0	41·0, 125·0	42·0, 96·0	34·0, 94·0
Body weight, kg
Mean(SD)	63·1(12·2)	61·8(12·2)	64·74(11·4)	63·99(11·1)
Range	42·0, 110·0	41·0, 125·0	42·0, 96·0	34·0, 94·0
BMI, kg/m [2]
Mean(SD)	24·18(3·67)	23·26(3·44)	24·06(3·23)	23·71(3·21)
Range	17·90, 33·95	17·07, 34·63	18·67, 33·61	15·95, 31·77
Time since diagnosis, months
Median(IQR)	16·5(2·5–56·5)	17·0(3·0–73·0)	18·0(2·0–81·0)	37·0(4·0–90·0)
Glucocorticoids within 4 weeks*
Yes	44(68·8%)	54(71·1%)	47(67·1%)	49(68·1%)
Median(IQR) platelet count × 10^9/L	14·00(6·00–21·00)	14·00(6·00–22·00)	14·00(6·00–23·00)	11·50(7·00–21·00)
Splenectomy
Yes	3(4·7%)	2(2·6%)	1(1·4%)	2(2·8%)
Platelet infusion within 1 week before enrollment
Yes	7(10·9%)	6(7·9%)	7(10·0%)	9(12·5%)
Bleeding
Yes	51(79·7%)	56(73·7%)	52(74·3%)	57(79·2%)
ITP-BAT bleeding score
Median(IQR)	2·0(1·0–3·0)	2·0(1·0–4·0)	2·0(1·0–3·0)	2·0(1·0–3·0)

Data are median (IQR), n (%), or n/total available (%) unless otherwise specified.

*Drugs used in at least 5% of the patients are listed.

Abbreviations: BMI, body mass index; IQR, interquartile range; ITP-BAT, primary immune thrombocytopenia-specific bleeding assessment tool; ITP, immune thrombocytopenia; rhTPO, recombinant human thrombopoietin.

Figure 2. Median platelet count over time (a) and median change in platelet count (b) from baseline on day 7, 14 and 28 in the FAS. Platelet count changes from baseline were analyzed using the analysis of covariance (ANCOVA) in which the baseline platelet count was used as a covariate, groups as a fixed effect, and centers as a random effect. ^day 7, P = .027; *day 14, P < .001; *day 28, P = .388.

Table II. Primary and secondary efficacy outcomes in the full analysis set (FAS).

Outcomes	7500-U QD (N=64)	15000-U QD (N=76)	15000-U QOD (N=70)	30000-U QOD (N=72)
Primary outcomes, day 14
N(missing)	64(0)	76(0)	70(0)	72(0)
CR	16(25·0%)	44(57·9%)	16(22·9%)	29(40·3%)
R	16(25·0%)	4(5·3%)	19(27·1%)	14(19·4%)
NR	26(40·6%)	23(30·3%)	26(37·1%)	14(19·4%)
NE	6(9·4%)	5(6·6%)	8(11·4%)	14(19·4%)
TRR, %(95% CI)	50·0%(37·8%–62·3%)	63·2%(52·3%–74·0%)	50·0%(38·3%–61·7%)	59·7%(48·4%–71·1%)
Difference in TRR vs· 7500-U QD, %(95%CI)	-	13·2%(−3·2%–29·5%)	0·0%(−16·95%–17·0%)	9·7%(−7·0%–26·4%)
Relapse	0	0	1(1·4%)	1(1·4%)
Secondary outcomes, day 7
N(missing)	64(0)	76(0)	70(0)	72(0)
CR	4(6·3%)	14(18·4%)	7(10·0%)	11(15·3%)
R	7(10·9%)	18(23·7%)	16(22·9%)	15(20·8%)
NR	44(68·8%)	29(38·2%))	40(57·1%)	31(43·1%)
NE	9(14·1%)	15(19·7%)	7(10·0%)	15(20·8%)
TRR, %(95% CI)	17·2%(7·9%–26·4%)	42·1%(31·0%–53·2%)	32·9%(21·9%–43·9%)	36·1%(25·0%–47·2%)
Difference in TRR vs· 7500-U QD, %(95% CI)	-	24·9%(10·5%–39·4%)	15·7%(1·3%–30·0%)	18·9%(4·5%–33·4%)
Secondary outcomes, day 28
N(missing)	50(14)	61(15)	58(12)	46(26)
CR	3(6·0%)	9(14·8%)	7(12·1%)	3(6·5%)
R	10(20·0%)	8(13·1%)	4(6·9%)	6(13·0%)
NR	19(38·0%)	15(24·6%)	23(39·7%)	8(17·4%)
NE	0	0	0	0
TRR, %(95% CI)	26·0%(I13·8%–38·2%)	27·9%(16·6%–39·1%)	19·0%(8·9%–29·1%)	19·6%(8·1%–31·0%)
Difference in TRR vs· 7500-U QD, %(95 CI)	-	1·9%(−14·7%–18·4%)	−7·0%(−22·8%–8·8%)	−6·4%(−23·2%–10·3%)
Relapse	18(36·0%)	29(47·5%)	24(41·4%)	29(63·0%)

Data are median (IQR), n (%), or n/total available (%) unless otherwise specified.

Abbreviations: CR, complete response; NE, not evaluable; NR, no response; R, response; rhTPO, recombinant human thrombopoietin; TRR, total response rate.

Definitions: CR: platelet count ≥100 × 10⁹/L and absence of bleeding; NR: a platelet count below 30 × 10⁹/L, or less than doubling baseline platelet counts, or the presence of bleeding post treatment; R: platelet count ≥30 × 10⁹/L with at least doubling baseline platelet count and absence of bleeding; relapse: a platelet count dip below 30 × 10⁹/L, less than doubling baseline platelet counts, or the presence of bleeding after achieving CR or R since day 7. The TRR is the proportion of patients achieving either CR or R.

Table III. Adverse events in the safety set.

Adverse events	7500-U QD (N = 64)	15000-U QD (N = 76)	15000-U QOD (N = 70)	30000-U QOD (N = 72)
All AEs	38(57·6%)	44(57·1%)	37(52·1%)	44(61·1%)
≥5%
Upper respiratory tract infection	3(4·6%)	2(2·6%)	5(7·0%)	6(8·3%)
Pneumonia	4(6·1%)	2(2·6%)	0	1(1·4%)
Fever	3(4·6%)	7(9·1%)	3(4·2%)	2(2·8%)
Fatigue	1(1·5%)	5(6·5%)	2(2·8%)	2(2·8%)
SAEs	3(4·6%)	4(5·2%)	0	3(4·2%)
Cerebral hemorrhage	0	0	0	1(1·4%)
Pharyngeal lesions	0	0	0	1(1·4%)
Immune thrombocytopenic purpura	0	2(2·6%)	0	1(1·4%)
Liver injury	1(1·5%)	0	0	0
Pneumonia	1(1·5%)	1(1·3%)	0	0
Upper respiratory tract infection	1(1·5%)	0	0	0
Fever	0	1(1·3%)	0	0
CTCAE ≥3 AEs	5(7·6%)	6(7·8%)	3(4·2%)	3(4·2%)
Cerebral hemorrhage	0	0	0	1(1·4%)
Insomnia	0	0	1(1·4%)	0
Headache	0	1(1·3%)	0	0
Bloating	0	0	0	1(1·4%)
Oral cavity bleeding	0	1(1·3%)	0	0
Immune thrombocytopenic purpura	0	2(2·6%)	1(1·4%)	1(1·4%)
Anemia	0	1(1·3%)	0	0
Iron deficiency anemia	1(1·5%)	0	0	0
Gingivitis	0	0	1(1·4%)	0
Pneumonia	2(3·0%)	1(1·3%)	0	0
Upper respiratory tract infection	1(1·5%)	1(1·3%)	0	0
Elevated blood pressure	1(1·5%)	0	0	0
Cutaneous bleeding	0	1(1·3%)	0	0
Hypertension	0	1(1·3%)	0	0
AEs causing treatment termination	2(3·0%)	2(2.6%)	1(1·4%)	3(4·2%)
Lacunar infarction	0	0	0	1(1·4%)
Lethargy	1(1·5%)	0	0	0
Headache	1(1·5%)	0	0	0
Pulmonary inflammation	0	0	0	1(1·4%)
Pharyngeal lesions	0	0	0	1(1·4%)
Chest discomfort	0	0	0	1(1·4%)
Chest pain	0	0	0	1(1·4%)
Upper abdominal pain	0	0	0	1(1·4%)
Oral cavity bleeding	0	1(1·3%)	0	0
Cutaneous bleeding	0	1(1·3%)	0	0
Immune thrombocytopenia	0	0	1(1·4%)	0

Data are n (%). Abbreviations: AEs, adverse events; SAEs, serious adverse events.

Nishimoto T, Kuwana M. Cd4+cd25+foxp3+ regulatory T cells in the pathophysiology of immune thrombocytopenia. Semin Hematol. 2013;50:S43–49. doi:10.1053/j.seminhematol.2013.03.018.

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