An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions

Figures & data

Table 1. Categorization of patients’ primary neurological conditions into disease groups (n).

AD/dementia (n = 17)		MS (n = 223)		Stroke/CBVD (n = 51)		ALS/MND (n = 199)		TBI (n = 23)		PD/movement disorders (n = 23)		Other PBA (n = 17)
AD	15	MS	223	Stroke	46	ALS	176	TBI	21	PD	11	Cerebellar ataxia	3
Frontal lobe  dementia	2			Venous angioma	1	Primary lateral sclerosis	16	Head trauma	2	Parkinson syndrome	1	Spinocerebellar ataxia	2
				Pontine AVM	1	Progressive bulbar palsy	5			Atypical PD	1	Cerebral palsy	2
				Post-cerebral aneurysm surgery	1	Bulbar motor neuron disease or degeneration	1			Parkinsonian syndrome	1	Chronic cough	1
				Brain aneurysm	1	Bulbar palsy	1			Progressive supranuclear palsy	5	Small-fiber neuropathy	1
				Subarachnoid hemorrhage	1					Huntington’s disease	1	Leuko-encephalopathy	1
										Choreiform disorder	1	Post-herpes simplex virus	1
										Movement disorder	1	Subdural hematoma	1
										Corticobasilar degeneration	1	Viral meningio-encephalitis	1
												Hydrocephalus	1
												Post-encephalitis	1
												Foster-Kennedy syndrome	1
												None known	1

AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; AVM: arteriovenous malformation; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; PBA: pseudobulbar affect; PD: Parkinson’s disease; TBI: traumatic brain injury.

Figure 1. Proportion of patients remaining in study, by study week.

Table 2. Patient disposition by primary neurological condition^a.

Patient disposition, n	AD/dementia	MS	Stroke/CBVD	TBI	ALS/MND	PD/movement disorders	Other PBA	Total
Enrolled	n = 17	n = 223	n = 51	n = 23	n = 199	n = 23	n = 17	N = 553
Treated ≥6 months	10	176	30	15	126	12	13	382
Treated ≥12 months^a	5	149	27	10	86	11	12	300
Completed treatment phase	4	149	27	9	85	10	12	296
Remaining at study termination	2	8	4	2	4	0	0	20
Did not complete due to:	11	66	20	12	110	13	5	257
AE	4	27	7	1	62	5	1	107
Medication refusal due to AE	2	10	4	2	18	4	1	41
Medication refusal for other than AE	0	7	1	2	3	0	1	14
Withdrew consent	3	15	3	3	9	1	0	34
Lost to follow-up	0	4	4	2	7	0	1	18
Protocol violation	0	2	0	0	1	0	0	3
Other	4	9	5	4	14	3	1	40
Entered extension phase	4	132	22	8	77	8	11	262

AD: Alzheimer’s disease; AE: adverse event; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; PBA: pseudobulbar affect; PD: Parkinson’s disease; TBI: traumatic brain injury.

^aIncludes all patients who completed the treatment phase or received at least 365 days of dosing.

Table 3. Patient demographics by primary neurological condition.

Category	AD/dementia (n = 17)	MS (n = 223)	Stroke/CBVD (n = 51)	TBI (n = 23)	ALS/MND (n = 199)	PD/movement disorders (n = 23)	Other PBA (n = 17)
Age (years)
Mean	63.5	45.7	54.8	45.6	55.6	64.9	49.1
SD	11.20	10.23	10.93	13.81	11.06	8.00	13.71
Median	66.0	47.0	56.0	44.0	57.0	66.0	52.0
Min, max	38, 79	18, 71	30, 80	18, 74	18, 80	50, 86	22, 67
Gender, n (%)
Male	10 (58.8)	49 (22.0)	24 (47.1)	10 (43.5)	116 (58.3)	15 (65.2)	7 (41.2)
Female	7 (41.2)	174 (78.0)	27 (52.9)	13 (56.5)	83 (41.7)	8 (34.8)	10 (58.8)
Ethnicity, n (%)
Caucasian	16 (94.1)	208 (93.3)	43 (84.3)	18 (78.3)	179 (89.9)	22 (95.7)	16 (94.1)
Black	1 (5.9)	5 (2.2)	5 (9.8)	1 (4.3)	5 (2.5)	0 (0)	0 (0)
Asian	0 (0)	1 (0.4)	1 (2.0)	0 (0)	1 (0.5)	0 (0)	0 (0)
Hispanic	0 (0)	8 (3.6)	2 (3.9)	3 (13.0)	9 (4.5)	1 (4.3)	1 (5.9)
Other	0 (0)	1 (0.4)	0 (0)	1 (4.3)	5 (2.5)	0 (0)	0 (0)

AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; PBA: pseudobulbar affect; PD: Parkinson’s disease; SD: standard deviation; TBI: traumatic brain injury.

Table 4. Common concurrent medications^a by primary neurological condition.

Description, %	AD/dementia (n = 17)	MS (n = 223)	Stroke/CBVD (n = 51)	TBI (n = 23)	ALS/MND (n = 199)	PD/movement disorders (n = 23)	Other PBA (n = 17)	Total (N = 553)
NSAIDs	23.5	36.3	19.6	30.4	40.2	17.4	5.9	33.8
Antidepressants	23.5	23.3	31.4	30.4	29.1	34.8	23.5	26.9
Tricyclic antidepressants	0	4.9	2.0	13.0	13.1	4.3	0	7.6
SSRIs	5.9	15.2	21.6	17.4	10.6	13.0	5.9	13.6
Other^b	17.6	8.1	7.8	8.7	10.1	17.4	17.6	9.8
Lipid modifiers	35.3	22.4	35.3	21.7	20.6	13.0	23.5	23.0
Antithrombotics	35.3	12.1	52.9	17.4	24.6	21.7	5.9	21.5
Analgesics (e.g., acetaminophen)	35.3	25.6	19.6	21.7	14.1	13.0	5.9	19.9
Drugs to inhibit gastric acid production	23.5	15.7	23.5	21.7	22.6	17.4	23.5	19.7
Vitamin E	11.8	7.6	3.9	4.3	37.7	8.7	29.4	18.8
Antiepileptics	17.6	23.8	25.5	43.5	9.0	8.7	29.4	18.8
Multivitamins, plain	5.9	22.4	7.8	8.7	20.1	0	11.8	17.9
Anxiolytics	23.5	16.6	11.8	13.0	20.1	21.7	11.8	17.5
Vitamin C	11.8	12.6	0	4.3	30.7	8.7	0	17.0
Antihistamines for systemic use	17.6	14.8	7.8	26.1	18.1	4.3	17.6	15.6
Vitamin B12 and folic acid	11.8	9.9	7.8	17.4	20.1	4.3	11.8	13.6
Calcium	5.9	20.2	7.8	8.7	7.5	17.4	5.9	13.0
Hypnotics and sedatives	17.6	8.5	3.9	4.3	20.6	17.4	0	12.7
Opioids	11.8	11.7	5.9	8.7	15.1	4.3	11.8	11.9
Laxatives	11.8	9.4	5.9	4.3	17.1	0	11.8	11.4
Misc. herbal	0	13.0	2.0	0	15.1	0	0	10.8
Beta-blocking agents	11.8	6.7	13.7	4.3	13.1	17.4	5.9	10.1
Thyroid preparations	17.6	9.4	9.8	17.4	7.5	13.0	5.9	9.4
ACE inhibitors, plain	17.6	5.8	19.6	13.0	9.0	4.3	11.8	9.0

ACE: angiotensin-converting enzyme; AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; NSAIDs: nonsteroidal anti-inflammatory drugs; PBA: pseudobulbar affect; PD: Parkinson’s disease; SSRI: selective serotonin reuptake inhibitor; TBI: traumatic brain injury.

^aUsed for ≥3 months and taken during the study; drug use represents minimum use in each category and may not include some combination products such as antihistamine cold products, combinations of vitamins and herbals, etc.

^bOther includes: venlafaxine, 3.6%; bupropion, 3.3%; trazodone, 2.5%; mirtazepine, 1.3%; duloxetine, mianserin, nefazodone, reboxetine, and hydroxytryptophan, 0.2% (1 patient) each.

Table 5. Common concurrent disease-specific medications^a by primary neurological condition.

AD/dementia (n = 17)	%
Anticholinesterase (e.g., donepezil)	47.1
Memantine	29.4
MS (n = 223)	%
Interferon beta	45.3
Glatiramer	27.4
Centrally acting muscle relaxants (e.g., baclofen,  tizanidine, orphenadrine)	33.2
Urinary antispasmodics (e.g., oxybutynin, tolterodine)	25.6
Psychostimulants (e.g., amphetamine derivatives,  modafinil, pemoline)	18.8
Glucocorticoids	5.8
Immunosuppressants (e.g., methotrexate,  mycophenolate, azathioprine)	5.8
Mitoxantrone	4.0
4-Aminopyridine	2.2
Stroke/CBVD (n = 51)	%
Aspirin	43.1
Clopidogrel	19.6
Calcium channel blockers (e.g., dihydropyridine)	11.8
TBI (n = 23)	%
Topiramate	13.0
Carbamazepine/oxcarbazepine	13.0
Thyroid preparations	17.4
Psychostimulants (e.g., amphetamine derivatives, modafinil, pemoline)	13.0
Antimigraine (e.g., triptans, selective 5HT1 agonists)	13.0
Glucocorticoids	8.7
ALS/MND (n = 199)	%
Riluzole	47.7
Centrally acting muscle relaxants (e.g., baclofen,  tizanidine, orphenadrine)	31.7
Coenzyme Q10	31.2
Tetracycline antibiotics (e.g., minocycline, doxycycline)	17.6
Creatine	15.6
Beta-2-adrenergic agonists, inhalants	14.6
Beta carotene/vitamin A	13.1
Urinary antispasmodics (e.g., oxybutynin, tolterodine)	11.1
Quinine	10.6
Expectorants and mucolytics (e.g., guaifenesin,  n-acetylcysteine)	9.0
Belladonna alkaloids (e.g., atropine, hyocyamine, scopolamine)	9.0
Glycopyrrolate	7.5
PD/movement disorders (n = 23)	%
Dopamine derivatives (± carbidopa, benserazide,  or entacapone)	65.2
Dopamine agonists	30.4
Amantadine	17.4
Selegiline	8.7
Trihexyphenidyl	0.5
Other PBA (n = 17)	%
Phenytoin	11.8
Tiagabine	11.8

5HT1: type 1 5-hydroxytryptamine (serotonin) receptor; AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; PBA: pseudobulbar affect; PD: Parkinson’s disease; TBI: traumatic brain injury.

^aUsed for ≥3 months and taken during the study.

Table 6. Incidence of adverse events reported by ≥5% and at least two patients in any primary-neurological-condition category (safety population).

Preferred term, % (n)	AD/dementia (n = 17)	MS (n = 223)	Stroke/ CBVD (n = 51)	TBI (n = 23)	ALS/MND (n = 199)	PD/movement disorders (n = 23)	Other PBA (n = 17)	p Value^a	Total (N = 553)
Any AE	70.6 (12)	89.7 (200)	90.2 (46)	82.6 (19)	98.0 (195)	91.3 (21)	88.2 (15)	0.0004	91.9 (508)
Nausea	11.8 (2)	23.8 (53)	19.6 (10)	13.0 (3)	31.7 (63)	8.7 (2)	23.5 (4)	0.0544	24.8 (137)
Headache	5.9 (1)	25.1 (56)	15.7 (8)	26.1 (6)	22.1 (44)	26.1 (6)	29.4 (5)	0.4613	22.8 (126)
Dizziness	5.9 (1)	21.5 (48)	19.6 (10)	21.7 (5)	17.1 (34)	30.4 (7)	17.6 (3)	0.5201	19.5 (108)
Fall	17.6 (3)	13.5 (30)	7.8 (4)	13.0 (3)	22.6 (45)	21.7 (5)	5.9 (1)	0.0674	16.5 (91)
Diarrhea	23.5 (4)	15.7 (35)	11.8 (6)	13.0 (3)	19.1 (38)	0 (0)	23.5 (4)	0.2426	16.3 (90)
Fatigue	17.6 (3)	16.6 (37)	7.8 (4)	39.1 (9)	11.1 (22)	13.0 (3)	17.6 (3)	0.0141	14.6 (81)
Weakness	0 (0)	14.8 (33)	3.9 (2)	4.3 (1)	18.6 (37)	4.3 (1)	11.8 (2)	0.0245	13.7 (76)
Nasopharyngitis	0 (0)	16.1 (36)	9.8 (5)	13.0 (3)	9.5 (19)	4.3 (1)	11.8 (2)	0.1944	11.9 (66)
Somnolence	5.9 (1)	4.9 (11)	15.7 (8)	4.3 (1)	15.6 (31)	26.1 (6)	11.8 (2)	0.0019	10.8 (60)
Arthralgia	0 (0)	14.3 (32)	5.9 (3)	0 (0)	10.1 (20)	13.0 (3)	5.9 (1)	0.1334	10.7 (59)
Cough	5.9 (1)	10.3 (23)	3.9 (2)	13.0 (3)	14.6 (29)	4.3 (1)	0 (0)	0.1633	10.7 (59)
Ecchymosis	5.9 (1)	8.1 (18)	5.9 (3)	4.3 (1)	12.6 (25)	13.0 (3)	17.6 (3)	0.4343	9.8 (54)
Pain in limb	0 (0)	13.0 (29)	11.8 (6)	0 (0)	8.5 (17)	0 (0)	5.9 (1)	0.1056	9.6 (53)
Constipation	11.8 (2)	5.4 (12)	5.9 (3)	0 (0)	15.1 (30)	4.3 (1)	11.8 (2)	0.0124	9.0 (50)
Insomnia	0 (0)	6.7 (15)	7.8 (4)	8.7 (2)	13.6 (27)	0 (0)	11.8 (2)	0.1004	9.0 (50)
Back pain	5.9 (1)	9.9 (22)	5.9 (3)	0 (0)	9.0 (18)	4.3 (1)	5.9 (1)	0.6684	8.3 (46)
Dysphagia	0 (0)	1.8 (4)	3.9 (2)	0 (0)	20.1 (40)	0 (0)	0 (0)	<0.0001	8.3 (46)
Dry mouth	5.9 (1)	5.8 (13)	9.8 (5)	0 (0)	8.5 (17)	13.0 (3)	0 (0)	0.4119	7.1 (39)
Edema lower limb	5.9 (1)	3.6 (8)	7.8 (4)	8.7 (2)	9.5 (19)	8.7 (2)	11.8 (2)	0.3244	6.9 (38)
Respiratory failure	0 (0)	0 (0)	0 (0)	0 (0)	19.1 (38)	0 (0)	0 (0)	<0.0001	6.9 (38)
Sore throat	5.9 (1)	9.0 (20)	3.9 (2)	4.3 (1)	7.0 (14)			0.4887	6.9 (38)
Urinary tract infection	0 (0)	9.9 (22)	5.9 (3)	4.3 (1)	4.5 (9)	4.3 (1)	11.8 (2)	0.2970	6.9 (38)
Dyspnea	0 (0)	3.6 (8)	3.9 (2)	8.7 (2)	11.6 (23)	4.3 (1)	5.9 (1)	0.0399	6.7 (37)
Fatigue aggravated	0 (0)	9.4 (21)	3.9 (2)	0 (0)	5.0 (10)	0 (0)	5.9 (1)	0.1663	6.1 (34)
Laceration	0 (0)	5.8 (13)	5.9 (3)	0 (0)	8.0 (16)	4.3 (1)	5.9 (1)	0.6724	6.1 (34)
MS aggravated	0 (0)	14.3 (32)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	<0.0001	5.8 (32)
Pyrexia	5.9 (1)	7.6 (17)	3.9 (2)		5.0 (10)	4.3 (1)	5.9 (1)	0.7549	5.8 (32)
Vomiting	5.9 (1)	7.6 (17)	2.0 (1)	8.7 (2)	5.0 (10)	4.3 (1)	0 (0)	0.6161	5.8 (32)
Muscle spasms	0 (0)	6.7 (15)	0 (0)	8.7 (2)	6.0 (12)	0 (0)	5.9 (1)	0.3610	5.4 (30)
Nasal congestion	0 (0)	6.3 (14)	3.9 (2)	4.3 (1)	6.0 (12)	0 (0)	0 (0)	0.6634	5.2 (29)
Anxiety	0 (0)	3.6 (8)	0 (0)	4.3 (1)	7.5 (15)	13.0	5.9 (1)	0.1138	5.1 (28)
Joint stiffness	0 (0)	5.4 (12)	2.0 (1)	0 (0)	6.5 (13)	0 (0)	11.8 (2)	0.3292	5.1 (28)

AD: Alzheimer’s disease; AE: adverse event; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; PBA: pseudobulbar affect; PD: Parkinson’s disease; TBI: traumatic brain injury.

^aChi-square test.

Table 7. Incidence of treatment-related^a adverse events by primary neurological condition (safety population).

Preferred term, %	AD/dementia (n = 17)	MS (n = 223)	Stroke/CBVD (n = 51)	TBI (n = 23)	ALS/MND (n = 199)	PD/movement disorders (n = 23)	Other PBA (n = 17)	Total (N = 553)
Any TRAE	23.5	39.9	51.0	47.8	59.3	60.9	52.9	49.0
Nausea	0	8.1	7.8	4.3	19.1	4.3	17.6	11.8
Dizziness (excluding vertigo)	0	10.3	7.8	13.0	10.1	21.7	17.6	10.5
Headache NOS	0	9.4	5.9	8.7	11.6	21.7	5.9	9.9
Somnolence	0	2.7	5.9	0	13.1	13.0	11.8	7.2
Fatigue	5.9	5.8	2.0	26.1	7.5	4.3	11.8	7.1
Diarrhea NOS	11.8	4.0	3.9	4.3	9.0	0	23.5	6.5
Dry mouth	0	3.1	5.9	0	8.0	8.7	0	5.1

Additional TRAEs that occurred in at least 5% of patients and in two or more patients in any disease category were stroke/CBVD: insomnia (not elsewhere classified), n = 3 (5.9%); TBI: lethargy, n = 3 (13.0%), abnormal dreams, n = 2 (8.7%); ALS/MND: constipation, n = 11 (5.5%); PD/movement disorders: confusion, n = 2 (8.7%); other PBA: joint stiffness, n = 2 (11.8%); flatulence, n = 2 (11.8%); dyspepsia, n = 2 (11.8%).

AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; NOS: not otherwise specified; PBA: pseudobulbar affect; PD: Parkinson’s disease; TRAE: treatment-related adverse event.

^aTRAEs that occurred in at least 5% of total patients; treatment-related categories included possible, probable, highly probable, and missing.