Treatment of Schizophrenia With L-tetrahydropalmatine (l-THP): a Novel Dopamine Antagonist With Anti-inflammatory and Antiprotozoal Activity

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT02118610
• Collaborator: Stanley Medical Research Institute (Other)
• Enrollment: 63
• Location: 1
• Arms: 2
• Duration (Months): 57
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

Schizophrenia is a devastating and complex illness, with multiple symptom and behavioral manifestations. Antipsychotic medications are the mainstay of treatment; however, many patients only partially respond to treatment. Development of new treatment has not progressed rapidly, in part, because the underlying etiopathophysiology of the illness is not well understood. To date, all pharmacological treatments approved for use in schizophrenia involve primary modulation of the dopamine system. Many agents without dopamine action have failed to demonstrate efficacy. There is growing evidence that schizophrenia may be, in part, due to an inflammatory process and pharmacological treatment approaches that decrease inflammation have shown promise. Thus, treatments that may have anti-inflammatory properties (e.g., TNF-alpha inhibition), but also possess dopamine modulation may prove to be beneficial. This novel medication, l-tetrahydropalmatine (l-THP), has robust anti-inflammatory properties, particularly TNF-alpha and ICAM inhibition; has antiprotozoal activity; and possesses an antipsychotic-like pharmacological profile of D1, D2 and D3 receptor antagonism. The high affinity of l-THP for D1 versus D2 receptors distinguishes it from first generation antipsychotics and its D1 to D2 ratio resembles that of the superior antipsychotic, clozapine. Also, an almost identical compound, l-stepholindine (l-SPD), demonstrates robust antipsychotic activity in humans (both positive and negative symptoms) and is currently used clinically in China. l-THP has been used for over 40 years clinically in China, has a good safety profile to date, and represents a novel and exciting mechanism for schizophrenia treatment. Initial safety data from our phase I study of l-THP (20 healthy controls) shows excellent tolerability and lack of any substantial side effects. L-THP has been tested in outpatient drug abuse trials for 4 weeks with good safety data, (Hu et al 2006, Yang et al 2003). Yang et al (2003) randomized this medication in over 120 participants for 4 weeks with 4 week observation without any notable side effects.

We will test this compound (30 mg BID) as an adjunct treatment in a randomized, double-blind, 4-week trial, in which we will assess treatment efficacy, changes in peripheral cytokine concentrations, and, secondarily, antiprotozoal effects, (antibody titers to Toxoplasma gondii), an infection that is known to occur at higher rates in schizophrenia than healthy controls and may be related in part to the illness.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: L-tetrahydropalmatine (30mg); Drug: Sugar pill	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Treatment of Schizophrenia With L-tetrahydropalmatine (l-THP): a Novel Dopamine Antagonist With Anti-inflammatory and Antiprotozoal Activity
• Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Dec 1, 2018
• Actual Study Completion Date: Jun 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: l-tetrahydropalmatine l-tetrahydropalmatine (30 mg BID)	Drug: L-tetrahydropalmatine (30mg); Active comparator
Placebo Comparator: Sugar Pill	Drug: Sugar pill; Placebo

Outcome Measures

Primary Outcome Measures

1. Positive and Negative Symptom Improvement [Baseline and 4 weeks (endpoint)]

   Measured by the Brief Psychiatric Rating Scale, positive symptom subfactor, Scale for the Assessment of Negative Symptoms (SANS) and Brief Negative Symptom Scale (BNSS). The total BPRS score is calculated by adding the scores for scales #1-#18. Each scale ranges from "1=Not Present" to "7=Very Severe". Total scores range from a minimum score of 18 to a maximum score of 126. A higher total score indicates a more severe psychiatric symptom rating.

Secondary Outcome Measures

1. Improvement in Cognitive Function [Baseline and 4 weeks (endpoint)]

   Neuropsychological testing will be done at baseline and endpoint using the MATRICS battery. A composite score as well as individual scores will be will be the outcome. This assessment total minimum score of -10 and maximum score of 80. The higher the score the better the outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. DSM-IV diagnosis of schizophrenia or schizoaffective disorder

2. Minimum score of 45 on the total Brief Psychiatric Rating scale or a CGI of 4

3. Age 18-64 years

4. Currently taking antipsychotic regimen with no dose changes in last 30 days

5. Ability to consent determined by a score of 10 or greater on the Evaluation to Sign Consent

Exclusion Criteria:

1. Women who are pregnant, nursing, or not using effective contraception (if capable of getting pregnant)

2. Current organic brain disorder or mental retardation

3. Medical condition whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with study medication. This includes HIV, kidney disease, congestive heart failure, pheochromocytoma, untreated hyperthyroidism, dehydration, fever, uncorrected congenital heart defect, seizures, electrolyte imbalance, uncontrolled diabetes mellitus, porphyria variegate, superventricular tachycardia, atrial fibrillation, cardiomyopathy, or cancer. This also may include other medical conditions where the medically accountable investigator in the study does not think it would be in the best interest of the participant to participate in the study.

4. Current (past month) substance abuse or dependence (DSM-IV criteria) other than nicotine or caffeine; substance use, per se, will not be exclusionary

5. Inability to provide valid informed consent

6. Inability to understand English

7. Inability to cooperate with study procedures

8. Taking herbal or homeopathic medications where the metabolism of the drug is not known

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Maryland Psyciatric Research Center	Catonsville	Maryland	United States	21228

Sponsors and Collaborators

• University of Maryland, Baltimore
• Stanley Medical Research Institute

Investigators

• Principal Investigator: Deanna L Kelly, Parm.D., BCPP, University of Maryalnd, Baltimore

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 17, 2018

More Information

Additional Information:

• Maryland Psychiatric Research Center

Publications

None provided.

• Responsible Party: Deanna Kelly, Deanna L. Kelly, Pharm.D., BCPP, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT02118610
• Other Study ID Numbers: HP-00058491
• First Posted: Apr 21, 2014
• Last Update Posted: Jan 6, 2022
• Last Verified: Jan 1, 2022

• Additional relevant MeSH terms: Schizophrenia; Tetrahydropalmatine

Study Results

Participant Flow

Arm/Group Title	L-tetrahydropalmatine	Sugar Pill
Arm/Group Description	l-tetrahydropalmatine (30 mg BID) L-tetrahydropalmatine (30mg): Active comparator	Sugar pill: Placebo
Period Title: Overall Study
STARTED	30	33
COMPLETED	29	32
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	L-tetrahydropalmatine	Sugar Pill	Total
Arm/Group Description	l-tetrahydropalmatine (30 mg BID) L-tetrahydropalmatine (30mg): Active comparator	Sugar pill: Placebo	Total of all reporting groups
Overall Participants	29	32	61
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	29 100%	32 100%	61 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.6 (11.1)	41.7 (10.1)	41.65 (10.52)
Sex: Female, Male (Count of Participants)
Female	9 31%	9 28.1%	18 29.5%
Male	20 69%	23 71.9%	43 70.5%
Race/Ethnicity, Customized (Number) [Number]
Black	18 62.1%	17 53.1%	35 57.4%
White	9 31%	13 40.6%	22 36.1%
Other	2 6.9%	2 6.3%	4 6.6%
Region of Enrollment (participants) [Number]
United States	29 100%	32 100%	61 100%

Outcome Measures

1. Primary Outcome

Title	Positive and Negative Symptom Improvement
Description	Measured by the Brief Psychiatric Rating Scale, positive symptom subfactor, Scale for the Assessment of Negative Symptoms (SANS) and Brief Negative Symptom Scale (BNSS). The total BPRS score is calculated by adding the scores for scales #1-#18. Each scale ranges from "1=Not Present" to "7=Very Severe". Total scores range from a minimum score of 18 to a maximum score of 126. A higher total score indicates a more severe psychiatric symptom rating.
Time Frame	Baseline and 4 weeks (endpoint)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-tetrahydropalmatine	Sugar Pill
Arm/Group Description	l-tetrahydropalmatine (30 mg BID) L-tetrahydropalmatine (30mg): Active comparator	Sugar pill: Placebo
Measure Participants	29	32
Baseline	41.3 (8.8)	40.3 (6.9)
Endpoint	36.6 (9.0)	37.3 (8.7)

2. Secondary Outcome

Title	Improvement in Cognitive Function
Description	Neuropsychological testing will be done at baseline and endpoint using the MATRICS battery. A composite score as well as individual scores will be will be the outcome. This assessment total minimum score of -10 and maximum score of 80. The higher the score the better the outcome.
Time Frame	Baseline and 4 weeks (endpoint)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-tetrahydropalmatine	Sugar Pill
Arm/Group Description	l-tetrahydropalmatine (30 mg BID) L-tetrahydropalmatine (30mg): Active comparator	Sugar pill: Placebo
Measure Participants	29	32
Baseline	28.0 (13.9)	27.7 (14.1)
Endpoint	28.8 (15.1)	29.0 (13.7)

Adverse Events

Time Frame	4 weeks
Arm/Group Title	L-tetrahydropalmatine		Sugar Pill
Arm/Group Description	l-tetrahydropalmatine (30 mg BID) L-tetrahydropalmatine (30mg): Active comparator		Sugar pill: Placebo
All Cause Mortality
	L-tetrahydropalmatine		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/32 (0%)
Serious Adverse Events
	L-tetrahydropalmatine		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		1/32 (3.1%)
Blood and lymphatic system disorders
Severe Neutropenia	0/29 (0%)	0	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	L-tetrahydropalmatine		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/29 (100%)		32/32 (100%)
Gastrointestinal disorders
Nausea	7/29 (24.1%)		9/32 (28.1%)
Diarrhea	6/29 (20.7%)		4/32 (12.5%)
Vomiting	3/29 (10.3%)		5/32 (15.6%)
General disorders
Sedation	9/29 (31%)		10/32 (31.3%)
Headache	9/29 (31%)		8/32 (25%)
Dizziness	9/29 (31%)		3/32 (9.4%)
Insomnia	6/29 (20.7%)		8/32 (25%)
Abdominal Pain	3/29 (10.3%)		5/32 (15.6%)
Constipation	3/29 (10.3%)		5/32 (15.6%)
Malaise	4/29 (13.8%)		8/32 (25%)
Restlessness	2/29 (6.9%)		7/32 (21.9%)
Salivation	5/29 (17.2%)		9/32 (28.1%)
Tinnitus	1/29 (3.4%)		7/32 (21.9%)
Dry Mouth	4/29 (13.8%)		9/32 (28.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.