Trial Outcomes & Findings for Clozapine for Cannabis Use in Schizophrenia (NCT NCT01639872)

Last Updated: 2020-05-05

Results Overview

Intensity of cannabis use is obtained each week retrospectively as the number of joints smoked during the prior week (assessed using the Timeline Followback). Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

49 participants

Primary outcome timeframe

12 weeks

Results posted on

2020-05-05

Participant Flow

During the course of the study a pharmacy issue precipitated the need to conduct the study as open label for a period of time. 7 participants (5 CLOZ and 2 RISP) were randomized under open label. Once a replacement pharmacy was in place the study returned to double blind status.

Participant milestones

Participant milestones
Measure	Clozapine The blinded CLOZ will be titrated on a recommended standard schedule, supervised by a study physician (or other prescriber) who can make the necessary adjustments to account for symptom control and tolerability. The titration is recommended to begin at 12.5 mg and then increase while the open-label base antipsychotic is tapered with a recommended goal of decreasing the base antipsychotic by 25% each week. If clinically tolerated, the target dose of CLOZ is 400 mg/day. Clozapine: Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day	Risperidone The blinded RISP will also be titrated in the first weeks, using a titration schedule, with a target dose of 4 mg/day, while the open label base antipsychotic is tapered in a similar fashion. Risperidone: Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day
Overall Study STARTED	24	25
Overall Study COMPLETED	14	20
Overall Study NOT COMPLETED	10	5

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Clozapine for Cannabis Use in Schizophrenia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Clozapine n=23 Participants The blinded CLOZ will be titrated on a recommended standard schedule, supervised by a study physician (or other prescriber) who can make the necessary adjustments to account for symptom control and tolerability. The titration is recommended to begin at 12.5 mg and then increase while the open-label base antipsychotic is tapered with a recommended goal of decreasing the base antipsychotic by 25% each week. If clinically tolerated, the target dose of CLOZ is 400 mg/day. Clozapine: Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day	Risperidone n=24 Participants The blinded RISP will also be titrated in the first weeks, using a titration schedule, with a target dose of 4 mg/day, while the open label base antipsychotic is tapered in a similar fashion. Risperidone: Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day	Total n=47 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	23 Participants n=93 Participants	24 Participants n=4 Participants	47 Participants n=27 Participants
Age, Categorical >=65 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Continuous	36.87 years STANDARD_DEVIATION 7.83 • n=93 Participants	41.54 years STANDARD_DEVIATION 9.58 • n=4 Participants	39.26 years STANDARD_DEVIATION 8.99 • n=27 Participants
Sex: Female, Male Female	1 Participants n=93 Participants	4 Participants n=4 Participants	5 Participants n=27 Participants
Sex: Female, Male Male	22 Participants n=93 Participants	20 Participants n=4 Participants	42 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=93 Participants	3 Participants n=4 Participants	9 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	17 Participants n=93 Participants	21 Participants n=4 Participants	38 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	7 Participants n=93 Participants	12 Participants n=4 Participants	19 Participants n=27 Participants
Race (NIH/OMB) White	15 Participants n=93 Participants	12 Participants n=4 Participants	27 Participants n=27 Participants
Race (NIH/OMB) More than one race	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Region of Enrollment United States	23 Participants n=93 Participants	24 Participants n=4 Participants	47 Participants n=27 Participants

PRIMARY outcome

Timeframe: 12 weeks

Population: Average number of joints Over Time was calculated using the midpoint of 6.5 weeks. NOTE: Outlying data for a CLOZ and RISP subject were removed from the analyses . Additionally, two subjects were excluded from the study due to unreliability (1 CLOZ, 1 RISP).

Outcome measures

Outcome measures
Measure	Clozapine n=22 Participants The blinded CLOZ will be titrated on a recommended standard schedule, supervised by a study physician (or other prescriber) who can make the necessary adjustments to account for symptom control and tolerability. The titration is recommended to begin at 12.5 mg and then increase while the open-label base antipsychotic is tapered with a recommended goal of decreasing the base antipsychotic by 25% each week. If clinically tolerated, the target dose of CLOZ is 400 mg/day. Clozapine: Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day	Risperidone n=23 Participants The blinded RISP will also be titrated in the first weeks, using a titration schedule, with a target dose of 4 mg/day, while the open label base antipsychotic is tapered in a similar fashion. Risperidone: Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day
Average Over Time of Intensity of Cannabis Use (Used to Evaluate Treatment Efficacy)	10.21 joints smoked during the prior week Interval 4.88 to 15.5	10.2 joints smoked during the prior week Interval 5.98 to 14.4

PRIMARY outcome

Timeframe: 12 weeks

Population: Average number of days of cannabis use over time was calculated using the midpoint 6.5 weeks. NOTE: Outlying data for a CLOZ and RISP subject were removed from the analyses. Additionally, two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).

Frequency of cannabis use is obtained each week retrospectively as the number of days of cannabis use during the prior week (assessed using the Timeline Followback). Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number.

Outcome measures

Outcome measures
Measure	Clozapine n=22 Participants The blinded CLOZ will be titrated on a recommended standard schedule, supervised by a study physician (or other prescriber) who can make the necessary adjustments to account for symptom control and tolerability. The titration is recommended to begin at 12.5 mg and then increase while the open-label base antipsychotic is tapered with a recommended goal of decreasing the base antipsychotic by 25% each week. If clinically tolerated, the target dose of CLOZ is 400 mg/day. Clozapine: Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day	Risperidone n=23 Participants The blinded RISP will also be titrated in the first weeks, using a titration schedule, with a target dose of 4 mg/day, while the open label base antipsychotic is tapered in a similar fashion. Risperidone: Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day
Average Over Time of Frequency of Cannabis Use	4.26 days of cannabis use during prior week Interval 3.4 to 5.12	4.58 days of cannabis use during prior week Interval 3.94 to 5.22

Adverse Events

Clozapine

Serious events: 3 serious events

Other events: 23 other events

Deaths: 0 deaths

Risperidone

Serious events: 3 serious events

Other events: 21 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Clozapine n=23 participants at risk The blinded CLOZ will be titrated on a recommended standard schedule, supervised by a study physician (or other prescriber) who can make the necessary adjustments to account for symptom control and tolerability. The titration is recommended to begin at 12.5 mg and then increase while the open-label base antipsychotic is tapered with a recommended goal of decreasing the base antipsychotic by 25% each week. If clinically tolerated, the target dose of CLOZ is 400 mg/day. Clozapine: Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day	Risperidone n=24 participants at risk The blinded RISP will also be titrated in the first weeks, using a titration schedule, with a target dose of 4 mg/day, while the open label base antipsychotic is tapered in a similar fashion. Risperidone: Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day
Psychiatric disorders Psychosis	13.0% 3/23 • Number of events 4 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	4.2% 1/24 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Gastrointestinal disorders Abdominal pain	4.3% 1/23 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	0.00% 0/24 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Respiratory, thoracic and mediastinal disorders Dyspnea	4.3% 1/23 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	0.00% 0/24 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Musculoskeletal and connective tissue disorders other-rhabdomyolisis	0.00% 0/23 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	4.2% 1/24 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Psychiatric disorders Suicidal ideation	0.00% 0/23 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	8.3% 2/24 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).

Other adverse events

Additional Information

Dr. Mary Brunette

Psychopharmacology Research Group

Phone: 603-271-5054

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Clozapine n=23 participants at risk The blinded CLOZ will be titrated on a recommended standard schedule, supervised by a study physician (or other prescriber) who can make the necessary adjustments to account for symptom control and tolerability. The titration is recommended to begin at 12.5 mg and then increase while the open-label base antipsychotic is tapered with a recommended goal of decreasing the base antipsychotic by 25% each week. If clinically tolerated, the target dose of CLOZ is 400 mg/day. Clozapine: Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day	Risperidone n=24 participants at risk The blinded RISP will also be titrated in the first weeks, using a titration schedule, with a target dose of 4 mg/day, while the open label base antipsychotic is tapered in a similar fashion. Risperidone: Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day
Blood and lymphatic system disorders Leukopenia	0.00% 0/23 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	8.3% 2/24 • Number of events 4 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Cardiac disorders Tachycardia	8.7% 2/23 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	0.00% 0/24 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Gastrointestinal disorders Abdominal pain	8.7% 2/23 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	0.00% 0/24 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Gastrointestinal disorders Constipation	17.4% 4/23 • Number of events 4 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	4.2% 1/24 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Gastrointestinal disorders Vomiting	13.0% 3/23 • Number of events 4 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	12.5% 3/24 • Number of events 3 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Gastrointestinal disorders other-Sialorrhea	43.5% 10/23 • Number of events 11 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	8.3% 2/24 • Number of events 3 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Metabolism and nutrition disorders hypercholesterolemia	8.7% 2/23 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	0.00% 0/24 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Metabolism and nutrition disorders Hyperglycemia	8.7% 2/23 • Number of events 3 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	0.00% 0/24 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Metabolism and nutrition disorders Hypertriglyceridemia	13.0% 3/23 • Number of events 3 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	4.2% 1/24 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Metabolism and nutrition disorders Increased appetite	0.00% 0/23 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	12.5% 3/24 • Number of events 3 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Metabolism and nutrition disorders weight gain	30.4% 7/23 • Number of events 8 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	12.5% 3/24 • Number of events 5 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Musculoskeletal and connective tissue disorders Back Pain	4.3% 1/23 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	8.3% 2/24 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Respiratory, thoracic and mediastinal disorders Cough	13.0% 3/23 • Number of events 4 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	0.00% 0/24 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Nervous system disorders Dizziness	17.4% 4/23 • Number of events 5 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	0.00% 0/24 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Nervous system disorders Extrpyramidal Effects	4.3% 1/23 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	8.3% 2/24 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Nervous system disorders Headache	8.7% 2/23 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	8.3% 2/24 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Nervous system disorders Insomnia	8.7% 2/23 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	4.2% 1/24 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Psychiatric disorders Sedation	21.7% 5/23 • Number of events 6 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	16.7% 4/24 • Number of events 4 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Psychiatric disorders Suicidal Ideation	8.7% 2/23 • Number of events 2 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	4.2% 1/24 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
Nervous system disorders Tremor	4.3% 1/23 • Number of events 1 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).	8.3% 2/24 • Number of events 3 • 6 months Two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).