The safety and tolerability of alkaloids from Alstonia scholaris leaves in healthy Chinese volunteers: a single-centre, randomized, double-blind, placebo-controlled phase I clinical trial

Figures & data

Figure 1. Study flow chart. SAD: Single ascending-dose, once daily; MAD: Multiple ascending-dose, three times daily; CALAS: Capsule of alkaloids from leaf of A. scholaris. The further tests of cohort 7 (600 mg) and 8 (720 mg) cohorts in SAD study were not conducted due to the occurrence of adverse reactions in cohort 6 (480 mg).

Table 1. Abnormal laboratory parameters after single ascending-dose administration.

Code	Items	Indices	Range	Pre-dosing	Post-dosing	Clinical significance	Retesting	Relatedness to treatment (decision of blinded adjudication committee)
Cohort 1-1	Liver function	ALP (IU/L)	51–160	46	50	No	Not performed	Unrelated
Cohort 1-2	Routine urinalysis	Urinary protein (g/L)	(−)	(−)	0.1 (±)	No	Not performed	Unrelated
Cohort 1-4	Hematologic analysis	Hb (g/L)	120–160	160	151	No	Not performed	Unrelated
	Liver function	ALT (IU/L)	<40	32	41	No	Not performed	Unrelated
Cohort 2-1	Hematologic analysis	RBC (×10^12/L)	4.3–5.8	5.69	5.92	No	Not performed	Unrelated
		Hb (g/L)	130–175	172	178	No	Not performed	Unrelated
	Routine urinalysis	Urinary protein (g/L)	(−)	0.1 (±)	0.1 (±)	No	Not performed	Unrelated
Cohort 2-2	Hematologic analysis	PLT (×10^9/L)	100–300	296	319	No	Not performed	Unrelated
	Routine urinalysis	Urinary protein (g/L)	(−)	(−)	0.1 (±)	No	Not performed	Unrelated
Cohort 2-3	Liver function	ALP (IU/L)	51–160	42	45	No	Not performed	Unrelated
Cohort 2-4	Hematologic analysis	N%	40–75	59.4	38.9	No	Not performed	Unrelated
		L%	20–50	33.4	52.4	No	Not performed	Unrelated
Cohort 2-5	Routine urinalysis	Urinary protein (g/L)	(−)	(−)	0.1 (±)	No	Not performed	Unrelated
		Urine alkone	(−)	(−)	±	No	Not performed	Unrelated
Cohort 2-7	Liver function	TP (g/L)	65–85	74	64.7	No	68.7	Unrelated
		ALB (g/L)	40–55	45.9	39.2	No	43.2	Unrelated
Cohort 2-8	Liver function	ALB (g/L)	40–55	48.4	39.4	No	43.9	Unrelated
Cohort 3-1	Liver function	ALP (IU/L)	51–160	53	49	No	Not performed	Unrelated
Cohort 3-3	Liver function	ALP (IU/L)	51–160	49	48	No	Not performed	Unrelated
Cohort 3-4	Liver function	ALP (IU/L)	51–160	51	44	No	Not performed	Unrelated
Cohort 3-5	Hematologic analysis	PLT (×10^9/L)	100–300	282	328	No	Not performed	Unrelated
	Routine urinalysis	Urine alkone	(−)	(−)	(±)	No	Not performed	Unrelated
Cohort 4-1	Routine urinalysis	Urinary protein (g/L)	(−)	0.2 (±)	0.2 (±)	No	0.1 (±)	Unrelated
Cohort 4-2	Routine urinalysis	Urinary protein (g/L)	(−)	(−)	0.1 (±)	No	Not performed	Unrelated
Cohort 4-3	Liver function	ALP (IU/L)	51–160	54	49	No	Not performed	Unrelated
Cohort 4-4	Hematologic analysis	PLT (×10^9/L)	100–300	268	319	No	Not performed	Unrelated
Cohort 4-7	Liver function	TBIL (μmol/L)	5.0–28.0	8.2	3.3	No	Not performed	Unrelated
Cohort 5-2	Hematologic analysis	N (×10^9/L)	1.8–6.3	3.60	6.46	No	Not performed	Unrelated
	Routine urinalysis	Urinary protein (g/L)	(−)	(−)	0.1 (±)	No	Not performed	Unrelated
Cohort 5-3	Liver function	ALP (IU/L)	51–160	35	34	No	Not performed	Unrelated
Cohort 5-4	Liver function	TBIL (μmol/L)	5.0–28.0	20.7	30.3	Yes	18.7	Possibly related
		IBIL (μmol/L)	< 20	15.6	22.4	Yes	13.0	Possibly related
Cohort 5-7	Hematologic analysis	RBC (×10^12/L)	3.8–5.1	4.96	5.33	No	Not performed	Unrelated
		Hb (g/L)	115–150	141	152	No	Not performed	Unrelated
Cohort 5-8	Hematologic analysis	PLT (×10^9/L)	100–300	371	398	No	Not performed	Unrelated
		L (×10^9/L)	1.1–3.2	2.07	3.33	No	Not performed	Unrelated
	Liver function	IBIL	<8.8	7.6	9.6	No	7.4	Possibly unrelated
Cohort 6-2	Routine urinalysis	Urinary protein (g/L)	(−)	0.1 (±)	0.1 (±)	No	Not performed	Unrelated
	Liver function	ALP (IU/L)	51–160	43	41	No	Not performed	Unrelated
Cohort 6-3	Liver function	TP (g/L)	65–85	69.6	61.6	No	68.6	Unrelated
		ALB (g/L)	40–55	45.5	39.7	No	45.3	Unrelated
		ALP (IU/L)	51–160	54	37	No	52	Unrelated
Cohort 6-5	Liver function	ALP (IU/L)	51–160	44	31	No	Not performed	Unrelated

−: Negative, ±: Doubtful, +: Positive.

‘Cohort number-number’ of code column represented the specific code of participant with abnormal laboratory parameters in each cohort.

Cohort 1: single ascending-dose, 8 mg per time and once daily; Cohort 2: single ascending-dose, 40 mg per time and once daily; Cohort 3: single ascending-dose, 120 mg per time and once daily; Cohort 4: single ascending-dose, 240 mg per time and once daily; Cohort 5: single ascending-dose, 360 mg per time and once daily; Cohort 6: single ascending-dose, 480 mg per time and once daily.

Table 2. Abnormal laboratory parameters after multiple ascending-dose administration.

Code	Items	Indices	Range	Pre-dosing	Post-dosing	Clinical significance	Retesting	Relatedness to treatment (decision of blinded adjudication committee)
Cohort 1-1	Routine urinalysis	Urinary protein (g/L)	(−)	(−)	0.2 (±)	No	(−)	Unrelated
Cohort 1-2	Hematologic analysis	PLT (×10^9/L)	100–300	305	323	No	343	Unrelated
		N%	40–75	43.5	34.7	No	43.1	Unrelated
		L%	20–50	43.4	54.2	No	46.0	Unrelated
Cohort 1-3	Hematologic analysis	N%	40–75	48.7	38.5	No	47.8	Unrelated
		L%	20–50	45.7	54.0	No	45.3	Unrelated
Cohort 1-4	Routine urinalysis	Urinary protein (g/L)	(−)	0.1 (±)	0.3 (1+)	No	(−)	Unrelated
	Liver function	GLB (g/L)	20.0–40.0	21.8	19.6	No	20.5	Unrelated
		ALP (IU/L)	51–160	54	49	No	48	Unrelated
Cohort 1-5	Routine urinalysis	Urinary protein (g/L)	(−)	(−)	0.1 (±)	No	Not performed	Unrelated
Cohort 1-6	Routine urinalysis	Urinary protein (g/L)	(−)	(−)	0.1 (±)	No	Not performed	Unrelated
Cohort 1-7	Hematologic analysis	N%	40–75	71.0	75.6	No	Not performed	Unrelated
Cohort 1-8	Routine urinalysis	WBC (/HP)	0–5	4	17	No	1	Unrelated
Cohort 2-3	Routine urinalysis	Urinary protein (g/L)	(−)	0.1 (±)	0.2 (±)	No	0.1 (±)	Unrelated

−: Negative, ±: Doubtful, +: Positive.

‘Cohort number-number’ of code column represented the specific code of participant with abnormal laboratory parameters in each cohort.

Cohort 1: multiple ascending-dose, 40 mg per time and three times daily for 7 days; Cohort 2: multiple ascending-dose, 120 mg per time and three times daily for 7 days.

Table 3. Adverse events profile with a single ascending-dose of CALAS.

TEAEs	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5		Cohort 6		Total
	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo
n (Missing)	4 (0)	2 (0)	6 (0)	2 (0)	6 (0)	2 (0)	6 (0)	2 (0)	6 (0)	2 (0)	6 (0)	2 (0)	34 (0)	12 (0)
Without (%)	4 (100.00)	2 (100.00)	6 (100.00)	2 (100.00)	6 (100.00)	2 (100.00)	5 (83.33)	1 (50.00)	5 (83.33)	2 (100.00)	0 (0.00)	1 (50.00)	26 (76.47)	10 (83.33)
With (%)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	1 (16.67)	1 (50.00)	1 (16.67)	0 (0.00)	6 (100.00)	1 (50.00)	8 (23.53)	2 (16.67)
Statistics
p-Value							0.46		1.00		0.25		1.00

Fisher’s exact test was used.

TEAEs: Treatment-emergent adverse events; n: the number of all participants; %: the percentage of participants with or without adverse reactions; Without: the number of cases without adverse events; With: the number of cases with adverse events.

Cohort 1: single ascending-dose, 8 mg per time and once daily; Cohort 2: single ascending-dose, 40 mg per time and once daily; Cohort 3: single ascending-dose, 120 mg per time and once daily; Cohort 4: single ascending-dose, 240 mg per time and once daily; Cohort 5: single ascending-dose, 360 mg per time and once daily; Cohort 6: single ascending-dose, 480 mg per time and once daily.

Table 4. Adverse events profile with a multiple ascending-dose of CALAS.

TEAEs	Cohort 1		Cohort 2		Total
	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo
n (Missing)	6 (0)	2 (0)	6 (0)	2 (0)	12 (0)	4 (0)
Without (%)	6 (100.00)	1 (50.00)	3 (50.00)	2 (100.00)	9 (75.00)	3 (75.00)
With (%)	0 (0.00)	1 (50.00)	3 (50.00)	0 (0.00)	3 (25.00)	1 (25.00)
Statistics
p-Value			0.46		1.00

Fisher’s exact test was used.

TEAEs: treatment-emergent adverse events; n: the number of all participants; Without: the number of cases without adverse events; With: the number of cases with adverse events; %: the percentage of participants with or without adverse reactions.

Cohort 1: multiple ascending-dose, 40 mg per time and three times daily for 7 days; Cohort 2: multiple ascending-dose, 120 mg per time and three times daily for 7 days.

Table 5. Adverse events with CALAS in grades.

Group	Items	Mild (n, %)		Moderate (n, %)		Severe (n, %)
		CALAS	Placebo	CALAS	Placebo	CALAS	Placebo
SAD	Abdominal distension	1 (2.94)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Hiccups	4 (11.76)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Loose stools	0 (0.00)	1 (8.33)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Increased bilirubin	1 (2.94)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Dry mouth	3 (8.82)	1 (8.33)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Nausea	3 (8.82)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
MAD	Diarrhoea (%)	0 (0.00)	1 (25.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Increased sleep (%)	3 (25.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Dizziness (%)	1 (8.33)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)

SAD: single ascending-dose; MAD: multiple ascending-dose.

The symbols n and % represented the participants with adverse reactions, with n indicating number and % indicating percentage.

Table 6. Adverse drug reactions profile with a single ascending-dose of CALAS.

ADRs	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5		Cohort 6		Total
	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo
n (Missing)	4 (0)	2 (0)	6 (0)	2 (0)	6 (0)	2 (0)	6 (0)	2 (0)	6 (0)	2 (0)	6 (0)	2 (0)	34 (0)	12 (0)
Without (%)	4 (100.00)	2 (100.00)	6 (100.00)	2 (100.00)	6 (100.00)	2 (100.00)	5 (83.33)	2 (100.00)	5 (83.33)	2 (100.00)	0 (0.00)	2 (100.00)	26 (76.47)	12 (100.00)
With (%)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	1 (16.67)	0 (0.00)	1 (16.67)	0 (0.00)	6 (100.00)	0 (0.00)	8 (23.53)	0 (0.00)
Statistics
p-Value										1.00

Fisher’s exact test was used.

ADRs: Adverse drug reactions; n: the number of all participants; Without: the number of cases without adverse reactions; With: the number of cases with adverse reactions; %: the percentage of participants with or without adverse reactions.

Cohort 1: single ascending-dose, 8 mg per time and once daily; Cohort 2: single ascending-dose, 40 mg per time and once daily; Cohort 3: single ascending-dose, 120 mg per time and once daily; Cohort 4: single ascending-dose, 240 mg per time and once daily; Cohort 5: single ascending-dose, 360 mg per time and once daily; Cohort 6: single ascending-dose, 480 mg per time and once daily.

Table 7. Adverse drug reactions profile with a multiple ascending-dose of CALAS.

ADRs	Cohort 1		Cohort 2		Total
	CALAS	Placebo	CALAS	Placebo	CALAS	Placebo
n (Missing)	6 (0)	2 (0)	6 (0)	2 (0)	12 (0)	4 (0)
With (%)	0 (0.00)	0 (0.00)	2 (33.33)	0 (0.00)	2 (16.67)	0 (0.00)
Without (%)	6 (100.00)	2 (100.00)	4 (66.67)	2 (100.00)	10 (83.33)	4 (100.00)
Statistics
p-Value			1.00		1.00

Fisher’s exact test was used.

ADRs: Adverse drug reactions; n: The number of all participants; With: the number of cases with adverse reactions; Without: the number of cases without adverse reactions; %: the percentage of participants with or without adverse reactions.

Cohort 1: multiple ascending-dose, 40 mg per time and three times daily for 7 days; Cohort 2: multiple ascending-dose, 120 mg per time and three times daily for 7 days.

Table 8. Adverse drug reactions in grades.

Group	Items	Mild (n, %)		Moderate (n, %)		Severe (n, %)
		CALAS	Placebo	CALAS	Placebo	CALAS	Placebo
SAD	Hiccups	4 (11.76)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Dry mouth	3 (8.82)	1 (8.33)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Nausea	3 (8.82)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Abdominal distension	1 (2.94)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Increased bilirubin	1 (2.94)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
MAD	Increased sleep (%)	2 (16.67)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)

SAD: single ascending-dose; MAD: multiple ascending-dose.

The symbols n and % stand for the participants with adverse reactions, with n indicating number and % indicating percentage.