Trial Outcomes & Findings for Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis (NCT NCT01802385)

NCT ID: NCT01802385

Last Updated: 2020-06-09

Results Overview

18-week survival. The comparison will be between sertraline 400mg group and placebo

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

460 participants

Primary outcome timeframe

18 weeks

Results posted on

2020-06-09

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Overall Study STARTED	231	229
Overall Study COMPLETED	125	109
Overall Study NOT COMPLETED	106	120

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Overall Study Death	106	120

Baseline Characteristics

Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=231 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Total n=460 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	231 Participants n=5 Participants	229 Participants n=7 Participants	460 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	35 years n=5 Participants	35 years n=7 Participants	35 years n=5 Participants
Sex: Female, Male Female	87 Participants n=5 Participants	97 Participants n=7 Participants	184 Participants n=5 Participants
Sex: Female, Male Male	144 Participants n=5 Participants	132 Participants n=7 Participants	276 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	231 Participants n=5 Participants	229 Participants n=7 Participants	460 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Uganda	231 participants n=5 Participants	229 participants n=7 Participants	460 participants n=5 Participants

PRIMARY outcome

Timeframe: 18 weeks

18-week survival. The comparison will be between sertraline 400mg group and placebo

Outcome measures

Outcome measures
Measure	Placebo n=231 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Survival	125 Participants	109 Participants

SECONDARY outcome

Timeframe: 18 weeks

Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions

Outcome measures

Outcome measures
Measure	Placebo n=231 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Safety (Occurence of Adverse Events)	121 events	141 events

SECONDARY outcome

Timeframe: 14 days

Number of participants with sterile cerebrospinal fluid at 2 weeks

Outcome measures

Outcome measures
Measure	Placebo n=231 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Count of Participants With Cerebrospinal Fluid Sterility	90 Participants	101 Participants

SECONDARY outcome

Timeframe: 14 weeks

Center for Epidemiologic Studies in Depression (CES-D) scale at 14 weeks. CES-D scores are based on a 20 item survey with total scores ranging from 0 to 60. Higher scores suggest a greater presence of depressive symptoms. A CES-D score of 16 or higher is interpreted to indicate a risk for depression.

Outcome measures

Outcome measures
Measure	Placebo n=231 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Center for Epidemiologic Studies in Depression (CES-D) Scale	16.6 score on a scale Interval 14.3 to 18.8	13.2 score on a scale Interval 11.0 to 15.5

SECONDARY outcome

Timeframe: 14 weeks

Quantitative neurocognitive performance Z-score (QNPZ-8) at 14 weeks. The QNPZ-8 is a mean score of testing of 8 neurocognitive domains. Eqach domain is scaled based on a Z-score where the mean = 0 for the HIV-negative Ugandan population, accounting for age and educational status. Each +1 unit is one standard deviation better than the population norm. Each -1 unit is one standard deviation worse than the population norm.

Outcome measures

Outcome measures
Measure	Placebo n=231 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Quantitative Neurocognitive Performance Score (QNPZ-8)	-1.4 score Interval -1.5 to -1.2	-1.3 score Interval -1.4 to 1.1

SECONDARY outcome

Timeframe: 14 days

To determine whether adjunctive sertraline will lead to a faster rate of fungal clearance from cerebrospinal fluid (CSF), as measured by early fungicidal activity (EFA) of clearance of the Cryptococcus colony forming units (cfu) per mL of CSF per day, compared to standard therapy alone.

Outcome measures

Outcome measures
Measure	Placebo n=231 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Fungal Clearance as Determined by Early Fungicidal Activity of CDF General Linear Regression	0.47 -log10 CFU/ml/day Interval 0.4 to 0.54	.43 -log10 CFU/ml/day Interval 0.37 to 0.5
Fungal Clearance as Determined by Early Fungicidal Activity of CDF Mixed-Effects Regression	0.33 -log10 CFU/ml/day Interval 0.3 to 0.35	.33 -log10 CFU/ml/day Interval 0.3 to 0.36

SECONDARY outcome

Timeframe: 18 weeks

Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse

Outcome measures

Outcome measures
Measure	Placebo n=231 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Number of Participants Experiencing IRIS OR Relapse	9 Participants	5 Participants

SECONDARY outcome

Timeframe: 18 weeks

Event free survival of composite events of: death,central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse.

Outcome measures

Outcome measures
Measure	Placebo n=231 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 Participants Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Event Free Survival	116 Participants	103 Participants

Adverse Events

Placebo

Serious events: 121 serious events

Other events: 65 other events

Deaths: 106 deaths

Sertraline 400mg

Serious events: 141 serious events

Other events: 66 other events

Deaths: 120 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=231 participants at risk Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 participants at risk Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
General disorders Non-serious Adverse Events	28.1% 65/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	28.8% 66/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.

Additional Information

Joshua Rhein

University of Minnesota

Phone: 612-624-1966

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Placebo n=231 participants at risk Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day). Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.	Sertraline 400mg n=229 participants at risk Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks. Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
General disorders Fever	1.7% 4/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.44% 1/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Infections and infestations Infection	1.3% 3/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.44% 1/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
General disorders Hypotension	0.43% 1/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.87% 2/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Thrombosis	0.43% 1/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.00% 0/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Gastrointestinal disorders Diarrhea	0.43% 1/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.00% 0/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Gastrointestinal disorders Vomiting	0.00% 0/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.44% 1/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Psychiatric disorders Altered Mental Status	0.43% 1/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	1.3% 3/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
General disorders Headache	0.43% 1/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.00% 0/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Nervous system disorders Seizure	0.87% 2/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.87% 2/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Respiratory, thoracic and mediastinal disorders Respiratory Distress	1.3% 3/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	1.7% 4/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Elevated Creatinine	3.9% 9/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	5.7% 13/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Hypokalemia	1.7% 4/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	5.7% 13/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Hyperkalemia	0.87% 2/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.00% 0/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Hyponatremia	5.6% 13/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	7.0% 16/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Hypernatremia	0.00% 0/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.87% 2/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Hypomagnesemia	0.87% 2/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.00% 0/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Acidosis	0.00% 0/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	1.3% 3/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Anemia	21.2% 49/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	23.6% 54/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Leukopenia	0.00% 0/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.44% 1/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Neutropenia	0.00% 0/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	1.7% 4/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.87% 2/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Lymphopenia	3.9% 9/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	4.4% 10/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Elevated ALT	0.87% 2/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.00% 0/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Elevated AST	1.3% 3/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.00% 0/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
Blood and lymphatic system disorders Elevated Bilirubin	4.3% 10/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	3.9% 9/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
General disorders Anorexia	0.43% 1/231 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.	0.00% 0/229 • 18 weeks Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.