Conditions: Schizophrenia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 214
Healthy volunteers: no

Brief summary:
This multicenter study assessed the effects of 24 weeks of basmisanil treatment on cognition and functioning of stable schizophrenia participants treated with antipsychotics.

Detailed description:

Arms:
arm 1: Participants received matching Placebo to Basmisanil orally twice daily for 24 weeks. arm 2: Participants received Basmisanil 80 mg orally twice daily (BID) for 24 weeks. arm 3: Participants received Basmisanil 240 mg orally twice daily (BID) for 24 weeks.

Interventions: intervention 1: Basmisanil intervention 2: Placebo
Intervention descriptions: intervention 1: Participants received either 80 milligrams (mg) or 240 mg of Basmisanil, as per the dosing schedules described above. intervention 2: Participants received matching Placebo to Basmisanil, as per the dosing schedules described above.

Protocol document:
Prot_000.pdf: 
 
Official Title: A Phase IIb, Multicenter, Randomized, Double-Blind, Parallel Group, 
Placebo-Controlled Study to Evaluate the Efficacy, Safety and 
Tolerability of Basmisanil (RO5186582) as Adjunctive Treatment in 
Patients With Cognitive Impairment Associated With Schizophrenia 
Treated With Antipsychotics 
NCT Number: NCT02953639 
Document Date: Protocol Version 5: 31-July-2018 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche, Inc. (or under its control) and therefore is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
Protocol BP39207, Version 5
PROTOCOL
TITLE:
A PHASE IIb, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PARALLEL GROUP, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE 
EFFICACY, SAFETY AND TOLERABILITY OF 
BASMISANIL (RO5186582) AS ADJUNCTIVE 
TREATMENT IN PATIENTS WITH COGNITIVE 
IMPAIRMENT ASSOCIATED WITH 
SCHIZOPHRENIA TREATED WITH 
ANTIPSYCHOTICS 
PROTOCOL NUMBER:
BP39207
VERSION:
5
P-IND NUMBER:
130290
TEST PRODUCT:
Basmisanil (RO5186582)
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 7 July 2016
DATES AMENDED:
Version 2: 21 September 2016
Version 3: 11 April 2017
Version 4: 28 November 2017
Version 5: See electronic date stamp below
 
31-Jul-2018 18:51:28
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
2/Protocol BP39207, Version 5
PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE IIb, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PARALLEL GROUP, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE 
EFFICACY, SAFETY AND TOLERABILITY OF 
BASMISANIL (RO5186582) AS ADJUNCTIVE 
TREATMENT IN PATIENTS WITH COGNITIVE 
IMPAIRMENT ASSOCIATED WITH 
SCHIZOPHRENIA TREATED WITH 
ANTIPSYCHOTICS
PROTOCOL NUMBER:
BP39207
VERSION NUMBER:
5
P-IND NUMBER:
130290
TEST PRODUCT:
Basmisanil (RO5186582)
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please keep the signed original form in your study files, and return a copy to your local Study Monitor.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
3/Protocol BP39207, Version 5
PROTOCOL AMENDMENT, VERSION 5:
RATIONALE
Protocol BP39207 has been amended to incorporate the following changes:

Clarification of positive Hepatitis B serology test results at screening (Section 4.2.3 
Exclusion Criterion #9 and laboratory assessments Section 4.6.1.6).
As described in File Note #7 dated 14 March 2018, a positive result at screening for 
hepatitis B (HBV) is an exclusion criterion. Patients with a positive result for 
Hepatitis B surface antigen (HBsAg +) at screening are not eligible for this study, as 
the study participant presents an active form of the disease and is infected. Results 
for hepatitis B core antibody (HBcAb) included in laboratory tests at screening 
inform about medical hepatitis B history. Positivity for anti-HBc (HBcAb +) together 
with a negative HBsAg (HBsAg -) points towards an immune signature due to 
natural infection and therefore such patients can be enrolled unless there is 
evidence of a clinically significant hepatic disorder at screening as per investigator 
assessment. 
Therefore, the test result for total hepatitis B core antibody (HBcAb) does not 
contribute to determination of eligibility but will continue to be performed for medical 
history purposes. This has now been clarified in the laboratory assessments section 
(Section 4.6.1.6).

Clarification of exclusionary ALT/AST/bilirubin results (Section 4.2.3 Exclusion 
Criterion #8).
As described in File Note #8 dated 5 April 2018: The formatting and syntax of the
protocol have been revised to more clearly reflect that the following findings
exclude patients from participation:
–
Elevated ALT and/or AST results > 2 ULN in combination with elevated
bilirubin>ULN.
–
Elevated serum creatinine > 1.5 ULN
Thefollowing findings do not constitute a reason to exclude patients from
participation, unless considered clinically significant by the Investigator:
–
An isolated ALT and/or AST result > 2 ULN
–
An isolated bilirubin result > ULN

Use of saliva test for alcohol (Section 4.6.1.6)
The protocol has been updated to show that alcohol may be tested using either 
urine or saliva. 




RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
5/Protocol BP39207, Version 5
Additional minor changes and corrections have been made to improve clarity and 
consistency. Substantial new information appears in italics. 




RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
7/Protocol BP39207, Version 5
Figure 1
Study Design
Screening
Study Drug Administration
Follow-up
5 weeks
24 weeks
4 weeks
The total duration of the study for each enrolled subject will be up to 34 weeks (from 
screening through completion of the last the last follow-up visit): 5-week Screening 
phase which includes a placebo test-phase, 24-week treatment period with study drug,
and 4-week follow-up period.
3.1.3.2
Efficacy IMC
Once approximately 90 patients, with a minimum of 30 patients per treatment arm (in 
case the 240 mg BID dose is stopped, patients in the 120 mg BID group will be added to 
the count of patients in the high dose group) have completed at least 12 weeks of 
treatment, and efficacy IMC (consisting of the members of the safety IMC along with the 
study translational medicine leader, a senior Roche clinical representative independent 
from the study team, a pharmacometrician, and others who will be involved in the 
decision-making process as needed) will conduct an interim analysis for futility on the 
primary endpoint of the study. The committee will review and evaluate the data 
unblinded at the group level (including global clinical impression and changes in positive 
and negative symptomatology, safety data and PK results if available), and the decision 
will be taken to either continue the study unchanged, to stop one arm or to end the study.
Descriptions of the conduct of the analysis, including pre-defined success criteria for the 
efficacy interim analysis, are summarized in Section 6.10 and will be described in further 
detail in a separate Efficacy IMC Agreement Document.
4.2.2
Inclusion Criteria
1. Male or female subjects aged between 18 and 50 years.
2.
Able to participate and willing to give written informed consent.
3. Able to understand key risk and benefits of the study as demonstrated by a score 
10 on the Evaluation to Sign Consent (ESC) form.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
8/Protocol BP39207, Version 5
4. Able to perform study assessments and procedures and comply with the study 
protocol, including one week of hospitalization/in-patient stay.
4.2.3
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from participation in the
study:
6. FSIQ 65<70 on the Wechsler Abbreviated Scale of Intelligence (WASI–II) at
screening.
7. Any clinically relevant ECG abnormalities at screening, including an average 
triplicate QTcF above 450 msec.
8.
Clinically significant abnormal vital signs or laboratory test results at screening.
Specifically, for the clinical chemistry parameters: 
o
the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
should not be >exceeding 2 times fold the upper limit of normal (ULN); in 
combination withand the total bilirubin > ULN with the exception of 
Gilbert syndrome
o
serum creatinine should not exceeding 1.5-fold ULN. 
9. Positive result at screening for hepatitis B (HBV), hepatitis C (HCV, untreated), or 
human immunodeficiency virus (HIV)-1 and -2. HCV patients who have been 
successfully treated and who test negative for HCV RNA, may be considered eligible 
for entry into the study. See Section 4.6.1.6, viral serology, laboratory assessments.
10. Concomitant use of prohibited medications (see Section 4.5.2). 
11. Moderate to severe substance use disorder (other than nicotine or caffeine), as 
defined by the DSM-5, within the last 12 months.
12. Confirmed positive test for alcohol or drugs of abuse at screening or at baseline.
13. Failure to detect blood concentrations of the prescribed antipsychotic medication.
IfIn case no commercial test is available for recently approved antipsychotics, the 
decision will be taken on a case by case basis between the Investigator and the 
Roche TML (or designee).
14. Subjects with a history of poor compliance in the last 2 years.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
9/Protocol BP39207, Version 5
4.4.2
Dosage and Administration
The study medication is two stick-packs taken orally, twice daily (in the morning and in 
the evening within 30 minutes of a meal) over 24 weeks. Granules should be mixed with 
or sprinkled onto a small amount soft food (i.e., yogurt, apple sauce, or pudding) and all 
of the food consumed to ensure accurate dosing. or as an alternative, patients have the 
option of placing the granules directly into their mouth followed by swallowing with a 
glass of water. (Note: the granules must not be mixed with water before putting them
into the mouth).
On Study Day 1, the first dose of medication will be administered in the hospital or at the 
clinic/study center once all pre-dose assessments have been conducted and eligibility 
has been confirmed. For all subsequent study visits, the morning dose will be taken at 
the study center. The last dose of medication will be the morning dose, administered at 
the clinic/study center at Week 24 visit.
Patients will be provided with a sufficient amount of medication to cover study treatment 
until the next site visit (including some overage). The qualified individual responsible for 
dispensing the study drug supply will prepare the correct medication supply required as 
instructed by IxRS and according to the randomization schedule. This individual will write 
the date dispensed and Patient Number on the study drug label and on the Drug 
Accountability Record. This individual will also record the study drug batch or lot number 
received by each subject during the study. 
Guidelines for treatment interruption or discontinuation are provided in Section 3.1.2 and 
Section 4.7.1.
4.4.3.1
Medication adherence system
The patient’s capacity to comply with taking twice daily study medication will be 
assessed during the screening period, between Baseline 1 and Baseline 2 visits. 
Patients will be asked to take placebo medication and to report each intake using a 
medication adherence monitoring platform (“Platform”) a web based platform/an app 
(provided on a smartphone). A compliance report will be made available to support the 
PI’s assessment of the patient’s capacity to comply with the study requirements (refer to 
Section 4.2.2, “Inclusion Criteria”).
This trial will employ a medication adherence monitoring platform (“Platform”). The 
Platform will either be provided to a patient pre loaded on a smartphone, or if possible 
the patient may download the Platform onto their own smartphone. Patients will receive 
a medication reminder at a time within a pre-defined window to take their medication. 
Patients will follow a series of prescribed steps using the front-facing camera in front of 
the front facing webcam of the smartphone to confirm patient identity and medication to 
be taken. The patient has to confirm ingestion of medication manually as well as the 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
10/Protocol BP39207, Version 5
chosen dosing method (i.e., soft food vs. direct intake) as soon as the platform has been 
updated to include this functionality. In addition, built-in reminders and a 
communication system allows real-time intervention in case of non-compliance. Use of 
this Platform will in no way supersede or replace the physician and/or prescribed 
medication protocol. Because the Platform does not change the medication protocol, but 
rather encourages adherence, use of this Platform presents minimal risk to the patients.
4.5.1
Permitted Therapy 
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter 
(OTC) drugs, approved dietary and herbal supplements, nutritional supplements and any 
non-medication interventions (e.g., individual psychotherapy, cognitive behavioral 
therapy, smoking cessation therapy, and rehabilitative therapy) used by a patient from 
screening until the follow-up visit. All concomitant medications should be reported to the 
Investigator and recorded on the Concomitant Medications electronic Case Report Form 
(eCRF).
All medication administered to manage AEs (including extrapyramidal symptoms such as 
dyskinesia or akathisia) should also be recorded on the Adverse Event eCRF.
Allowed concomitant therapy, including medications used for the treatment of 
stablechronic medical conditions other than schizophrenia that are allowed, must be on 
a stable dosing regimen for 6 weeks prior to screening and remain stable throughout the 
study (from screening to last follow-up visit. Dose adjustments that are required as part 
of routine treatment to control the chronic condition (such as dose adjustments of 
insulin or anti-hypertensive medication) are permitted. Any changes in antipsychotic 
therapy, for management of worsening of symptoms or initiation of additional 
pharmacotherapy including antidepressant after randomization may be permitted on a 
case by case basis, in consultation between the PI and the Medical Monitor/Sponsor. 
The reason for such changes should be appropriately documented.
4.5.2
Prohibited Therapy
 
 
Diphenhydramine
Diphenhydramine is not permitted because of potential cardiac effects.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
11/Protocol BP39207, Version 5
Dofetilide
Dofetilide use is not permitted because of the potential for interaction between 
basmisanil and renally-cleared cationic drugs, as well as the very narrow therapeutic 
window of dofetilide. 
Anticholinergic medications
Anticholinergic (e.g., benztropine, biperiden, or trihexyphenidyl) are prohibited during the 
trial due to potential negative impact on cognition and the potential to interfere with the 
study primary endpoint. Anticholinergics prescribed as prophylaxis treatment for 
extrapyramidal symptoms need to be washed-out prior to enrollment. If deemed 
necessary by the PI, beta blockers (e.g. propranolol) can be prescribed instead.
Clozapine, Diphenhydramine, Direct oral anticoagulants (dabigatran etexilate, 
edoxaban, apixaban and rivaroxaban) and Colchicine
Not permitted in this study.
4.6.1.5
Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. Laboratory safety tests shall be collected at time-points specified 
in the Schedule of Assessments (Appendix 1).
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor patient’s safety. Where the clinical significance of abnormal 
lab results is considered uncertain, screening lab tests may be repeated before 
randomization to confirm eligibility. If there is an alternative explanation for a positive 
urine or blood test for drugs of abuse, e.g., previous occasional and acute intake of a 
medication or food containing for example, codeine, benzodiazepines or opiates, the test 
could be repeated to confirm washout. Furthermore, in case of a positive test for a drug 
of abuse at screening, that can be explained by prescribed and permitted co-medication 
(see Section 4.5.1), a positive result at screening is not systematically exclusionary and 
will be evaluated on a case by case basis.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the local or central laboratory.
Samples collected before dosing or from patients on placebo are to be taken as a 
precautionary measure and may not be analyzed in the first instance.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
12/Protocol BP39207, Version 5
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to the Sponsor for analysis. Instruction manuals and supply kits will be 
provided for all central laboratory assessments.

Hematology (leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential 
count [neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells]).

Serum chemistry (sodium, potassium, chloride, bicarbonate, glucose, urea, 
creatinine, protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, 
AST, urate, lactate dehydrogenase [LDH]).

Coagulation (international normalized ratio [INR], activated partial thromboplastin 
time [aPTT], prothrombin test [PT]).

Viral serology
o
HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, HIV-2 antibody).
o
Hepatitis B (surface antigen (HBsAg determines HBV positivity whereas 
total hepatitis B core antibody (HBcAb) will be tested for but results do 
not contribute to eligibility assessment.)
o
Hepatitis B surface antigen (HBsAg).
Total hepatitis B core antibody (HBcAb).
o
Hepatitis C virus (HCV) antibody. In cases where hepatitis C was 
successfully treated, a positive HCV serology result can be followed by 
HCV RNA testing

Lipids (cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein 
[HDL] cholesterol, triglycerides).

Pregnancy test: All women of childbearing potential (including those who have had a 
tubal ligation) will have a blood or urine pregnancy test as outlined in the Schedule 
of Assessments (Appendix 1). 

Drug and alcohol screen:
Urine or saliva drug screen will be performed at time points indicated in Appendix 1. 
Agents tested for are at a minimum: opiates, amphetamines, cocaine, 
hallucinogens, PCP, and cannabis and alcohol. An alcohol breath saliva test can be 
performed at any time during the study at the PIs discretion.

Benzodiazepine assessment: Benzodiazepine levels will be measured in blood 
samples as described in Appendix 1 (see Section 4.5.2 on use of GABAA PAMs). 
4.6.2.2
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
13/Protocol BP39207, Version 5
An Evaluation to Sign Consent (ESC) form will be used to ensure patients' 
understanding of the study. The form consists of 6 questions rated on a 0 to 2 scale for 
the level of understanding and participants are required to score at least 10 out of a 
possible 12 in order to participate in the study. It may be necessary to review the 
consent documents with the patient multiple times and repeat the ESC to ensure this 
degree of comprehension (maximum of 3 times). 
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that patients meet all eligibility criteria. The Investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure.
6.3.2
Efficacy Analysis Population
Per-Protocol Population
The PP population will be precisely defined in the statistical analysis plana separate 
document, before database closure, as the subset of the ITT population without major 
protocol deviations. 
6.10
Interim Analyses
An interim analysis will be conducted when approximately 30 patients per arm have 
completed the first 12 weeks of treatment. The analysis will be conducted by the efficacy 
IMC as described in Section 3.1.3.2.
This analysis will focus on the change from baseline to Week 12 in MCCB 
neurocognitive composite score, which will be analyzed using an MMRM model which 
will be similar to that described for the primary analysis (including all stratification factors 
although this may not be possible depending on the actual cell size). The pairwise 
comparison of each active dose to placebo will be evaluated using the estimated effect 
size based on the least-squares mean (LSM) estimates from the MMRM models. For 
each dose arm, the decision whether to continue or drop the arm for the remainder of 
the study will be based on the posterior conditional probability that the true treatment 
effect size for that arm is0.35. If the calculated conditional posteri
probability is less 
than 20% that the true treatment effect size can reach this threshold for one of the two 
doses, then that dose arm may be discontinued. If this conditional posterior probability 
is less than 20% for both dose arms, then the study may be discontinued for futility. A 
informative prior will be used for the posterior probability calculations.
In case the calculated conditional posteri
probability that the true treatment effect size 
can reach the threshold of effect size > 0.35 is more than 20% for both treatment arms, 
one treatment arm may still be discontinued. 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
14/Protocol BP39207, Version 5
Further analysis details on the interim analysis will be documented in a separate 
Efficacy IMC Agreement Document prior to the conduct of the interim analysis.
8.2 Informed Consent
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site. If applicable, it will be provided in a certified translation of the 
local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission. The final IRB/EC‑approved Consent Forms must be provided to the 
Sponsor for Health Authority submission purposes according to local requirements.
In this study, the informant will be asked to provide information useful to assess patient 
eligibility and to complete clinician rated scales. A separate written informed consent will 
be obtained from the informant.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
In this study, the Investigator or Designee shall assess the capacity of the patient to give 
informed consent while discussing the study and the Consent Forms. This assessment 
shall be confirmed by the results of the ESC form (see Inclusion Criteria Section 4.2.2) 
and the IQ measure (see Exclusion Criteria #6, Section 4.2.3) done during the Screening 
Visit.
10
References
Investigator’s Brochure, Basmisanil (RO5186582)-GABAA 5 negative allosteric 
modulator, Version 9, Addendum 1,10, October 2017June 2018.
Appendix 1 Schedule of Assessments
The Schedule of Assessments has been updated to include the Evaluation to Sign 
Consent at Screening.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
15/Protocol BP39207, Version 5
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
PROTOCOL SYNOPSIS .................................................................................... 21
1.
BACKGROUND AND RATIONALE ............................................................ 35
1.1
Background on Disease......................................................... 35
1.2
Background on Basmisanil .................................................... 35
1.2.1
Previous Non-Clinical Studies ............................................... 36
1.2.1.1
Non-Clinical Pharmacology ................................................... 36
1.2.1.2
Non-Clinical Pharmacokinetics and Metabolism.................... 37
37
1.2.2
Previous Clinical Studies ....................................................... 38
1.2.2.1
Safety and Tolerability ........................................................... 39
40
1.3
Study Rationale and Benefit–Risk Assessment..................... 41
1.3.1
Study Rationale ..................................................................... 41
1.3.2
Benefit-Risk Assessment....................................................... 41
2.
OBJECTIVES.............................................................................................. 42
2.1
Primary Objectives ................................................................ 42
2.2
Secondary Objectives............................................................ 42
2.3
Exploratory Objectives........................................................... 43
3.
STUDY DESIGN......................................................................................... 43
3.1
Description of Study .............................................................. 43
3.1.1
Overview of Study Design ..................................................... 43
3.1.2
Stopping Rules ...................................................................... 45
3.1.3
Internal Monitoring Committees (IMCs) ................................. 46
3.1.3.1
Safety IMC............................................................................. 46
3.1.3.2
Efficacy IMC .......................................................................... 47
3.1.4
End of Study.......................................................................... 47
3.2
Rationale for Study Design.................................................... 48
3.2.1
Rationale for Dosage Selection ............................................. 48
3.2.2
Rationale for Study Population .............................................. 48


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
16/Protocol BP39207, Version 5
3.2.3
Rationale for Biomarker Assessments................................... 48
3.3
Outcome Measures ............................................................... 49
3.3.1
Safety Outcome Measures .................................................... 49
3.3.2
Pharmacokinetic (PK) Outcome Measures............................ 50
3.3.3
Efficacy Outcome Measures.................................................. 50
3.3.4
Patient-Reported Outcome Measures ................................... 50
3.3.5
Exploratory Outcome Measures ............................................ 50
4.
MATERIALS AND METHODS .................................................................... 51
4.1
Center.................................................................................... 51
4.2
Study Population ................................................................... 51
4.2.1
Recruitment Procedures........................................................ 51
4.2.2
Inclusion Criteria.................................................................... 51
4.2.3
Exclusion Criteria................................................................... 52
4.3
Method of Treatment Assignment and Blinding..................... 53
4.4
Study Treatment.................................................................... 54
4.4.1
Formulation, Packaging, and Handling.................................. 54
4.4.2
Dosage and Administration.................................................... 55
4.4.3
Medication Adherence and Engagement 
Systems................................................................................. 55
4.4.3.1
Medication adherence system............................................... 55
4.4.3.2
Optional patient engagement system .................................... 56
4.4.4
Investigational Medicinal Product Accountability ................... 57
4.4.5
Post-Trial Access to Basmisanil ............................................ 58
4.5
Concomitant Therapy and Food ............................................ 58
4.5.1
Permitted Therapy................................................................. 58
4.5.2
Prohibited Therapy ................................................................ 59
4.6
Study Assessments ............................................................... 61
4.6.1
Description of Study Assessments ........................................ 61
4.6.1.1
Medical and Psychiatric History and 
Demographic Data................................................................. 61
4.6.1.2
Physical Examinations........................................................... 62
4.6.1.3
Vital Signs.............................................................................. 62
4.6.1.4
Electrocardiograms................................................................ 62


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
17/Protocol BP39207, Version 5
4.6.1.5
Laboratory Assessments ....................................................... 63
4.6.1.6
Pharmacokinetic Assessments.............................................. 64
4.6.1.7
Genotyping and Biomarker Assessments.............................. 64
4.6.1.8
Disease-Specific Assessments.............................................. 65
4.6.1.9
Samples for Research Biosample Repository
(RBR)..................................................................................... 71
4.6.2
Timing of Study Assessments ............................................... 74
4.6.2.1
Order of Assessments ........................................................... 74
4.6.2.2
Screening and Pre-treatment Assessments .......................... 74
4.6.2.3
Assessments during Treatment............................................. 75
4.6.2.4
Early Termination Assessments ............................................ 75
4.6.2.5
Follow-Up Assessments ........................................................ 75
4.7
Patient, Study, and Site Discontinuation................................ 75
4.7.1
Patient Discontinuation.......................................................... 75
4.7.1.1
Discontinuation from Study Drug........................................... 76
4.7.1.2
Withdrawal from Study........................................................... 76
4.7.2
Study and Site Discontinuation.............................................. 76
5.
ASSESSMENT OF SAFETY....................................................................... 77
5.1
Safety Parameters and Definitions ........................................ 77
5.1.1
Adverse Events ..................................................................... 77
5.1.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 78
5.1.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 78
5.1.4
Selected Safety Assessments ............................................... 79
5.2
Safety Plan ............................................................................ 79
5.2.1
Management of Specific Adverse Events .............................. 80
5.2.1.1
Changes in Heart Rate and Blood Pressure.......................... 80
5.2.1.2
Changes in QTcF Interval...................................................... 80
5.2.1.3
Increases in Serum Creatinine .............................................. 80
5.2.1.4
Suicidality .............................................................................. 80
5.2.1.5
Withdrawal Symptoms........................................................... 81
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 81


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
18/Protocol BP39207, Version 5
5.3.1
Adverse Event Reporting Period ........................................... 81
5.3.2
Eliciting Adverse Event Information....................................... 81
5.3.3
Assessment of Severity of Adverse Events ........................... 82
5.3.4
Assessment of Causality of Adverse Events ......................... 82
5.3.5
Procedures for Recording Adverse Events............................ 82
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 82
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 83
5.3.5.3
Persistent or Recurrent Adverse Events................................ 83
5.3.5.4
Abnormal Laboratory Values ................................................. 83
5.3.5.5
Abnormal Vital Sign Values ................................................... 84
5.3.5.6
Abnormal Liver Function Tests.............................................. 85
5.3.5.7
Deaths ................................................................................... 85
5.3.5.8
Preexisting Medical Conditions.............................................. 85
5.3.5.9
Worsening of Symptoms Associated with 
Schizophrenia........................................................................ 86
5.3.5.10
New occurrence or worsening of Extrapyramidal 
Symptoms (EPS)................................................................... 86
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 86
5.3.5.12
Overdoses ............................................................................. 87
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 87
5.4.1
Emergency Medical Contacts................................................ 88
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 88
5.4.3
Reporting Requirements for Pregnancies.............................. 88
5.4.3.1
Pregnancies in Female Participants ...................................... 88
5.4.3.2
Pregnancies in Female Partners of Male Study 
Subjects................................................................................. 88
5.4.3.3
Abortions ............................................................................... 89
5.4.3.4
Congenital Anomalies/Birth defects....................................... 89
5.5
Follow-Up of Patients after Adverse Events .......................... 89
5.5.1
Investigator Follow-Up........................................................... 89
5.5.2
Sponsor Follow-Up ................................................................ 89


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
19/Protocol BP39207, Version 5
5.6
Post-Study Adverse Events................................................... 90
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 90
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 90
6.1
Determination of Sample Size ............................................... 90
6.2
Summaries of Conduct of Study............................................ 91
6.3
Analysis Populations ............................................................. 91
6.3.1
Safety Analysis Population .................................................... 91
6.3.2
Efficacy Analysis Population.................................................. 91
6.4
Summaries of Treatment Group Comparability ..................... 91
6.5
Safety Analyses..................................................................... 91
6.5.1
Adverse Events ..................................................................... 92
6.5.2
Clinical Laboratory Test Results............................................ 92
6.5.2.1
Standard Reference Ranges and Transformation 
of Data................................................................................... 92
6.5.2.2
Definition of Laboratory Abnormalities................................... 92
6.5.3
Vital Signs.............................................................................. 93
6.5.4
ECG Data Analysis................................................................ 93
6.5.5
Concomitant Medications ...................................................... 93
6.6
Efficacy Analyses .................................................................. 93
6.6.1
Primary Efficacy Endpoint...................................................... 93
6.6.2
Secondary Efficacy Endpoints............................................... 94
6.7
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 94
6.8
Patient-Reported Outcome Analyses .................................... 94
6.9
Exploratory Analyses............................................................. 95
6.10
Interim Analyses .................................................................... 95
7.
DATA COLLECTION AND MANAGEMENT ............................................... 96
7.1
Data Quality Assurance......................................................... 96
7.2
Electronic Case Report Forms............................................... 96
7.3
Source Data Documentation.................................................. 97
7.4
Use of Computerized Systems .............................................. 98
7.5
Retention of Records............................................................. 98


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
20/Protocol BP39207, Version 5
8.
ETHICAL CONSIDERATIONS.................................................................... 98
8.1
Compliance with Laws and Regulations ................................ 98
8.2
Informed Consent.................................................................. 98
8.3
Institutional Review Board or Ethics Committee.................... 99
8.4
Confidentiality...................................................................... 100
8.5
Financial Disclosure ............................................................ 100
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 100
9.1
Study Documentation .......................................................... 100
9.2
Site Inspections ................................................................... 101
9.3
Administrative Structure....................................................... 101
9.4
Publication of Data and Protection of Trade 
Secrets ................................................................................ 101
9.5
Protocol Amendments ......................................................... 102
10. REFERENCES ......................................................................................... 103
LIST OF TABLES
Table 1
Items comprising the “Positive symptoms” and 
Excitement/Hostility” Marder factors ........................................... 70
Table 2
Adverse Event Severity Grading Scale ....................................... 82
LIST OF FIGURES
Figure 1
Determination of the Schizophrenia Cognitive Subtype at 
Screening.................................................................................... 44
Figure 2
Study Design............................................................................... 45
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 108
Appendix 2
Antipsychotics Equivalent Dose................................................ 111
Appendix 3
Examples of prohibited CYP3A4 inhibitors and inducers 
concomitant medication ............................................................ 115
Appendix 4
Common Terminology Criteria for Adverse Events (CTCAE): 
QTc Criteria............................................................................... 116


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
21/Protocol BP39207, Version 5
PROTOCOL SYNOPSIS
TITLE:
A PHASE IIB, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PARALLEL GROUP, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE 
EFFICACY, SAFETY AND TOLERABILITY OF 
RO5186582 AS ADJUNCTIVE TREATMENT IN 
PATIENTS WITH COGNITIVE IMPAIRMENT 
PROTOCOL NUMBER:
BP39207
VERSION:
5
P-IND NUMBER:
130290
TEST PRODUCT:
Basmisanil (RO5186582)
PHASE:
IIB
INDICATION:
Cognitive impairment associated with schizophrenia
SPONSOR:
F. Hoffmann-La Roche Ltd.
OBJECTIVES 
Primary Objectives
The primary objective of this study is:

To investigate the efficacy of 24 weeks of basmisanil treatment on cognitive function as 
measured by the MATRICS consensus cognitive battery (MCCB) neurocognitive composite 
score, in stable patients with cognitive impairment associated with schizophrenia (CIAS) 
treated with antipsychotics.
Secondary Objectives
The secondary objectives for this study are as follows:
To evaluate the effect of 24 weeks of treatment with basmisanil in stable patients with CIAS 
treated with antipsychotics on the following:

Individual cognitive domains of the MCCB, namely attention, speed of processing, 
reasoning, working memory, visual learning, verbal learning and social cognition.

Additional specific hippocampal and prefrontal-dependent cognitive tasks and processes 
(as measured by the Trail making test [TMT]-B, Wechsler memory scale - Fourth edition, 
verbal paired associates [WMS IV-PAL] and Wechsler memory scale - Fourth edition, 
logical memory test [WMS IV-LM]).

Functional capacity and performance (as measured by the Personal and Social 
Performance scale [PSP] and Schizophrenia Cognition Rating Scale [SCoRS]).

To evaluate the safety and tolerability of 24 weeks of basmisanil treatment in patients with 
CIAS treated with antipsychotics.

To characterize the steady-state pharmacokinetics (PK) of basmisanil and its metabolites, if 
appropriate, in stable patients with CIAS treated with antipsychotics using population PK 
modelling methods.
Exploratory Objectives
The exploratory objectives for this study are as follows:

To explore the effect of 24 weeks of treatment with basmisanil on semantic priming 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
22/Protocol BP39207, Version 5
(measured in the category fluency test of the MCCB) and primacy/recency effects 
(measured in the Hopkins verbal learning test of the MCCB), two experimental measures of 
hippocampal-dependent cognitive processes.

To determine whether the patients’ genetic profile predicts effects of treatment with 
basmisanil on cognitive functions.

To evaluate the effect of 24 weeks of treatment with basmisanil on smartphone-based self-
reported mood, sleep, subjective well-being and cognitive functioning.

To evaluate the effect of 24 weeks of treatment with basmisanil on functional capacity 
assessed by novel computerized measures and “work readiness”.

To evaluate the effect of 24 weeks of treatment with basmisanil on symptoms of 
schizophrenia including positive and negative symptoms.

To evaluate the effect of 24 weeks of treatment with basmisanil on quality of life.
STUDY DESIGN
Description of Study
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled, Phase IIb 
study, to evaluate the effects of 24 weeks of basmisanil treatment in stable patients with CIAS 
treated with antipsychotics. 
The final analysis will investigate the PK, safety and tolerability, and efficacy of 24 weeks of 
basmisanil treatment on cognition and functioning.
Two doses of basmisanil (240 mg, 80 mg) will be tested against placebo. Approximately 231
patients will be randomized to one of three treatment arms, in a 1:1:1 ratio:

Arm 1: 240 mg BID (may be lowered to 120 mg BID upon Safety Internal Monitoring 
Committee [IMC] decision).

Arm 2: 80 mg BID.

Arm 3: Placebo BID.
Randomization will be stratified based on age, sex and “schizophrenia cognitive subtype”. The 
stratification threshold for age will be 35 years and 35 years. The “schizophrenia cognitive 
subtype” will be determined at screening based on the difference between the pre-morbid 
intelligence quotient (IQ), estimated by the wide range assessment test (WRAT)-4 reading test 
standard score, and current full scale IQ scores (FSIQ), estimated by the Wechsler Abbreviated 
Scale of Intelligence – second edition (WASI-II).
The study will be divided into 3 phases:

A screening phase of approximately 5 weeks which includes Baseline 1 and Baseline 2 
visits.

A double-blind treatment phase with study drug, of approximately 24 weeks.

A follow-up phase of approximately 4 weeks after treatment discontinuation.
Efficacy, safety, and PK assessments will be conducted throughout the study, as detailed in the 
Schedule of Assessments.
Patients will be treated until the end of the study treatment period, unacceptable toxicities, or 
withdrawal of consent.
NUMBER OF PATIENTS
A total of up to 231 patients will be enrolled in the study, to ensure that a minimum of 
150 patients (50 patients per treatment arm) will have evaluable data at 24 weeks. They will be 
randomized 1:1:1 to the three study arms. The sample size may be increased if the actual 
premature withdrawal rate is higher than expected.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
23/Protocol BP39207, Version 5
TARGET POPULATION
The study population consists of male and female subjects with schizophrenia aged 18 to 50 
years who are on stable antipsychotic therapy.
INCLUSION/EXCLUSION CRITERIA
Inclusion criteria
Patients must meet the following criteria for study entry:
1.
Male or female subjects aged between 18 and 50 years.
2.
Able to participate and willing to give written informed consent.
3.
Able to understand key risk and benefits of the study as demonstrated by a score 10 
on the Evaluation to Sign Consent (ESC) form.
4.
Able to perform study assessments and procedures and comply with the study protocol, 
including one week of hospitalization/in-patient stay.
5.
Diagnosis of schizophrenia of any type utilizing the Mini International Neuropsychiatric 
Interview (MINI) and Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition, (DSM-5) direct clinical assessments, family informants and past medical 
records.
6.
Evidence of stability of symptoms for 3 months at screening, i.e., without 
hospitalizations for schizophrenia or increase in level of psychiatric care due to 
worsening of symptoms of schizophrenia.
7.
Schizophrenia clinical symptom severity defined by the following: Hallucinatory 
Behavior item score 5 and a Delusion item score 5 of the Positive and Negative 
Syndrome Scale (PANSS).
8.
On a stable regimen of antipsychotic therapy for at least 3 months at screening and 
receiving no more than two antipsychotics. Antipsychotic regimen: Patients must be on 
a "primary" antipsychotic and may be on a secondary antipsychotic. The amount of the 
secondary antipsychotic has to be equal to or less than the equivalent dose of the 
primary antipsychotic and the sum of the primary and secondary antipsychotics must 
be 6 mg of risperidone equivalents. 
9.
Has an identified informant, considered reliable by the Investigator, (or designee), to 
provide support to the patient to help ensure compliance with study treatment, study 
visits and protocol procedures. The informant should know the patient for at least 
3 months, see the patient outside of the clinical context on a weekly basis, and should 
be able to provide information on the patient helpful for completing study rating scales.
The informant should be available for telephone interviews throughout the study and 
attend study visits when possible.
10. Fluent in English.
11. A body mass index (BMI) between 18 and 38 kg/m2 inclusive.
12. For women of childbearing potential: Use contraceptive methods (hormonal or 
non-hormonal) that result in a failure rate of 1% per year during the treatment period 
and for at least 28 days after the last dose of study drug. 
Note: A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a post-menopausal state (12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). Examples of contraceptive methods with a failure 
rate of 1% per year include bilateral tubal ligation, male sterilization, established 
proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
24/Protocol BP39207, Version 5
intrauterine devices, and copper intrauterine devices.
Exclusion criteria
Patients who meet any of the following criteria will be excluded from participation in the study:
1.
Pregnant or lactating.
2.
Current DSM-5 diagnosis other than schizophrenia including bipolar disorder, 
schizoaffective disorder and major depressive disorder (MDD).
3.
Clinically significant metabolic, hepatic, hematological, pulmonary, cardiovascular, 
gastrointestinal or urological disorder.
4.
Any history of diagnosed seizure disorder.
5.
Clinically significant neurological illness or significant head trauma that affects cognitive 
function, in the judgment of the Principal Investigator (PI).
6.
FSIQ 65<70 on the Wechsler Abbreviated Scale of Intelligence (WASI–II) at 
screening.
7.
Any clinically relevant ECG abnormalities at screening, including an average triplicate 
QTcF above 450 msec.
8.
Clinically significant abnormal vital signs or laboratory test results at screening.
Specifically, Ffor the clinical chemistry parameters: 
  the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
exceeding 2 fold the upper limit of normal (ULN) in combination with the total 
bilirubin > ULN with the exception of Gilbert syndrome;
  serum creatinine exceeding 1.5-fold ULN. 
9.
Positive result at screening for hepatitis B (HBV), hepatitis C (HCV, untreated), or 
human immunodeficiency virus (HIV)-1 and -2. HCV patients who have been 
successfully treated and who test negative for HCV RNA, may be considered eligible for 
entry into the study. See Section 4.6.1.6, viral serology, laboratory assessments.
10. Concomitant use of prohibited medications (see Section 4.5.2). 
11. Moderate to severe substance use disorder (other than nicotine or caffeine), as defined 
by the DSM-5, within the last 12 months.
12. Confirmed positive test for alcohol or drugs of abuse at screening or at baseline.
13. Failure to detect blood concentrations of the prescribed antipsychotic medication. If no 
commercial test is available for recently approved antipsychotics, the decision will be 
taken on a case by case basis between the Investigator and the Roche TML (or 
designee).
14. Subjects with a history of poor compliance in the last 2 years.
15. Subjects who have experienced a change in their living situation in the last 3 months 
which would preclude the availability of a reliable informant.
16. Suicide attempt within one year or currently at risk of suicide in the opinion of the 
Investigator.  
17. Receipt of an investigational drug within 3 months prior to screening.
18. Any medical condition or other factors, as judged by the Investigator, which may 
interfere with the subjects’ participation or his/her ability to participate in this study.
19. A planned hospitalization during the time of the study (i.e., for elective surgery. Note 
that the one-week in-patient stay for the first approximately 40 patients is not 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
25/Protocol BP39207, Version 5
exclusionary).
LENGTH OF STUDY
The total duration of the study for each enrolled subject will be up to 34 weeks (from screening 
through completion of the last the last follow-up visit): 5-week Screening phase which includes 
a placebo test phase, 24-week treatment period with study drug, and 4-week follow-up period.
END OF STUDY
The end of the study is defined as the date when the Last Patient, Last Observation (LPLO) 
occurs. LPLO is expected to occur approximately 28 weeks after enrollment of the last study 
subject.
OUTCOME MEASURES
SAFETY OUTCOME MEASURES
The safety outcome measures for this study are as follows:

Incidence, nature and severity of adverse events (AEs).

Incidence, nature and severity of treatment discontinuations due to AEs.

Change from baseline in Systolic (SBP) and diastolic blood pressure (DBP) and pulse rate 
(PR).

The following ECG parameters will be obtained: HR, PQ (PR), QRS, QT, RR and QTcF 
along with information on T- and U-waves.

Changes in ECG parameters as compared to baseline ECG.

Incidence of clinically significant ECG abnormalities.

Incidence of laboratory abnormalities, based on hematology, clinical chemistry, and 
urinalysis test results:
o
Hematology: Hemoglobin, hematocrit, erythrocytes (RBC), platelets, leukocytes (WBC) 
differential (counts): neutrophils, eosinophils, lymphocytes, monocytes, basophils.
–
Blood chemistry: Aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), total and conjugated bilirubin, alkaline phosphatase (ALP), albumin, 
creatinine, urea, total protein, total cholesterol, triglycerides, sodium, chloride, 
calcium, phosphate, potassium, glucose.
o
Urinalysis: protein, blood, glucose, leukocytes, nitrites and pH.

The Extrapyramidal Symptom Rating Scale – abbreviated version (ESRS-A).

The PANSS items comprising the positive symptoms and hostility/excitement factors (for in-
patients only).

Suicidality assessed by the Columbia Suicide Severity Rating Scale (C-SSRS).

The Nurse’s Observation Scale for In-patient Evaluation - 30 items (NOSIE-30) (for in-
patients only).
PHARMACOKINETIC OUTCOME MEASURES
The PK outcome measures are:

Population and individual primary PK parameters estimation (e.g., apparent clearances and 
volumes) and the influence of various covariates on these parameters.

Secondary PK parameters (e.g., area under the curve [AUC] and Cmax) derived from the 
individual post-hoc predictions.
EFFICACY OUTCOME MEASURES
The efficacy outcomes measures for this study are:

MCCB neurocognitive composite score.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
26/Protocol BP39207, Version 5

WMS IV-PAL score.

WMS IV-LM score.

Trail Making test part B (TMT-B) and part A (TMT-A).

Personal and Social Performance (PSP) scale. 

Schizophrenia Cognition Rating Scale (SCoRS).

Clinical global impression – severity (CGI-S).

Clinical global impression – improvement (CGI-I).
PATIENTREPORTED OUTCOME MEASURES
The patient-reported outcome measures for this study are as follows:

Schizophrenia Quality of Life Scale (SQLS).

Smartphone-based Likert scales evaluating mood, sleep, subjective well-being and 
cognitive functioning and treatment expectancy.
EXPLORATORY OUTCOME MEASURES
The exploratory outcome measures for this study include but are not limited to the following:

Positive and Negative Syndrome Scale (PANSS).

Brief Negative Symptom Scale (BNSS).

The Category Fluency test of the MCCB (semantic priming).

The Hopkins Verbal Learning Test of the MCCB (primacy and recency effects).

Virtual Reality Functional Capacity Assessment Tool (VRFCAT).

University of Miami Computerized Functional Assessment System (CFAS).

The work readiness questionnaire (WoRQ).
BIOMARKER/GENOTYPING SAMPLE COLLECTION
Two whole blood samples will be collected for (1) Research Biosample Repository (RBR) long-
term storage for e.g., future genotyping for consortia contributions, and (2) DNA extraction for 
genotyping those genes associated with cognition, brain plasticity, and gamma-aminobutyric 
acid (GABA)- and glutamatergic functioning, as well as the complement C4 copy number 
variants (CNVs).
INVESTIGATIONAL MEDICINAL PRODUCT(S)
Test product
The study drug basmisanil will be provided in an immediate-release granule formulation 
packaged in sachets (“stick-packs”) containing 40 mg or 120 mg of basmisanil per sachet; two 
sachets to be administered orally twice daily.
Placebo
The placebo will be provided in a matching formulation, to be administered according to the 
same schedule as the study drug.
PROCEDURES
Informed consent will be obtained prior to any study-specific procedures. Following eligibility at 
screening (including Evaluation to Sign Consent [ESC]) and confirmation at baseline, patients 
will be enrolled into the study. The assessments and examinations will be conducted as 
described in the Schedule of Assessments.
The first approximately 40 eligible patients will be enrolled in the study as in-patients and will 
remain under supervision in the hospital for the first week of dosing. During this period, 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
27/Protocol BP39207, Version 5
additional assessments will be conducted as described in the Schedule of Assessments.
STATISTICAL METHODS
PRIMARY ANALYSIS
The primary analysis population for all efficacy analyses will be based on the ITT population, 
which will include all randomized patients treated with study medication. The primary efficacy 
endpoint (change from baseline to Week 24 in MCCB neurocognitive composite score) will be 
analyzed using a mixed effect model for repeated measures (MMRM) with treatment, region, 
age group, sex, schizophrenia cognitive subtype, and visit as fixed effects, treatment-by-visit 
interaction term, and baseline value as the covariate. The model will include subject as a 
random effect, and incorporate an unstructured variance-covariance matrix. For each active 
dose arm tested at the final analysis, this model will be used to test the null hypothesis of no 
treatment difference between the placebo arm and the active arm at a 2-sided -level of 0.1.
SAFETY ANALYSES
All safety analysis will be based on the safety analysis population.
As appropriate, listings, summary tables and graphs will be provided for safety and tolerability 
assessments, including:

Incidence of AEs (overall, by intensity and by relationship to study medication).

Incidence of SAEs.

Incidence of laboratory abnormalities (including hematology, clinical chemistry, and 
urinalysis parameters).

Incidence of blood pressure (BP) abnormalities.

Incidence of ECG abnormalities as well ECG changes as compared to baseline 
measurements.

Changes in the PANSS as compared to baseline.

NOSIE-30 as compared to baseline.

Changes in C-SSRS as compared to baseline.
Safety data will be summarized using descriptive statistics using the safety analysis population, 
which will include all patients treated.
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Individual and mean plasma concentrations at each sampling time-point will be presented by 
listings and descriptive summary statistics, including means, medians, geometric means, 
ranges, standard deviations, and coefficients of variation. Individual and mean plasma 
concentration versus time data will be plotted on semi-logarithmic scales.
Graphical exploration of the relationship between basmisanil (and M1 and other metabolites, if 
relevant), exposure and outcome measures as well as safety parameters will be performed. If 
indicated by such exploration, more formal analyses of PK to pharmacodynamics (PD) 
parameters of interest may be undertaken.
PATIENT-REPORTED OUTCOME ANALYSES
The patient reported outcomes are:

Change from baseline on the patient-reported health-related quality of life scale (SQLS).

Change in subjective mood, sleep and subjective well-being and cognitive functioning 
ratings.
These endpoints will be analyzed using an MMRM model similar to that described for the 
primary endpoint, and summarized using descriptive statistics.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
28/Protocol BP39207, Version 5
EXPLORATORY ANALYSES
The exploratory analyses will include:

Mean change from baseline in the PANSS factor and total scores.

Mean change from baseline in the BNSS subscales and total scores.

Mean change from baseline in % of patients rated as “ready to work” on the WoRQ.

Mean change from baseline in the VRFCAT score.

Mean change from baseline in the CFAS score.

Semantic priming analysis of verbal fluency, as described in Section 4.6.1.9. 

Primacy region analysis of episodic verbal learning and recall. Percentage recall from the 
primacy relative to the recency region will be calculated for each learning trial and for long-
delay free recall. 

Analysis of genetic PRS and complement C4 CNV as described in Section 3.2.3, and the 
15q11-q13 chromosomal region including the GABRs GABRB3, GABRB5 and GABRG3 
genes.
These endpoints will be analyzed using an MMRM or ANCOVA model as appropriate, and 
summarized using descriptive statistics.
SAMPLE SIZE JUSTIFICATION
A sample size of 50 patients per arm provides 80% power to detect a treatment effect size of 
0.5, at a 2-sided -level of 0.1, for the pairwise comparison of each active dose arm to placebo. 
No adjustments for multiple comparisons will be incorporated into the analysis. Incorporating an 
assumed premature rate of 35%, a study sample size of 231 (77 patients per arm) will be used. 
The sample size may be increased if the actual premature rate is higher than expected.
Interim Analyses
An interim analysis will be conducted when approximately 30 patients per arm have completed 
the first 12 weeks of treatment. The analysis will be conducted by the efficacy IMC.
This analysis will focus on the change from baseline to Week 12 in MCCB neurocognitive 
composite score, which will be analyzed using an MMRM model which will be similar to that 
described for the primary analysis (including all stratification factors although this may not be 
possible depending on the actual cell size). The pairwise comparison of each active dose to 
placebo will be evaluated using the estimated effect size based on the least-squares mean 
(LSM) estimates from the MMRM models. For each dose arm, the decision whether to continue 
or drop the arm for the remainder of the study will be based on the conditional probability that 
the true treatment effect size for that arm is 0.35. If the calculated conditional probability is 
less than 20% that the true treatment effect size can reach this threshold for one of the two 
doses, then that dose arm may be discontinued. If this conditional probability is less than 20% 
for both dose arms, then the study may be discontinued for futility. 
In case the calculated conditional probability that the true treatment effect size can reach the 
threshold of effect size > 0.35 is more than 20% for both treatment arms, one treatment arm 
may still be discontinued. 
Further analysis details on the interim analysis will be documented in a separate Efficacy 
IMC Agreement Document prior to the conduct of the interim analysis.
LIST OF PROHIBITED MEDICATIONS
Prohibited therapies should not be administered during the time period from at least 5 days (or 5 
half-lives, whichever is longer) prior to initiation of study treatment until the end of the follow-up 
period, unless otherwise specified.




RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
30/Protocol BP39207, Version 5
Diphenhydramine
Diphenhydramine is not permitted because of potential cardiac effects.
Dofetilide
Dofetilide use is not permitted because of the potential for interaction between basmisanil and 
renally-cleared cationic drugs, as well as the very narrow therapeutic window of dofetilide. 
Anticholinergic medications
Anticholinergic (e.g. benztropine, biperiden, or trihexyphenidyl) are prohibited during the trial 
due to potential negative impact on cognition and the potential to interfere with the study 
primary endpoint. Anticholinergics prescribed as prophylaxis treatment for extrapyramidal 
symptoms need to be washed-out prior to enrollment. If deemed necessary by the PI, beta 
blockers (e.g. propranolol) can be prescribed instead.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
31/Protocol BP39207, Version 5
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
Adverse events
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
BACS
Brief assessment of cognition in schizophrenia
BID
Bis in die (twice daily)
BMI
Body mass index
BNSS
Brief negative symptom scale
BP
Blood pressure
BUN
Blood urea nitrogen
CFAS
Computerized functional assessment system
CGI-I
Clinical global impression – improvement
CGI-S
Clinical global impression – severity
CIAS
Cognitive impairment associated with schizophrenia
CL
Clearance
CNS
Central nervous system
CNV
Copy number variant
CRO
Contract research organization
C-SSRS
Columbia suicide severity rating scale
CYP
Cytochrome P450
DBP
Diastolic blood pressure
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid
DSM
Diagnostic and Statistical Manual
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 
fifth edition
DSUR
Development Safety Update Report
EC
Ethics committee
ECG
Electrocardiograms
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European Economic Area
EEG
Electroencephalogram
ePRO
Electronic patient-reported outcome


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
32/Protocol BP39207, Version 5
EPS
Extrapyramidal symptoms
ESC
Evaluation to sign consent
ESF
Eligibility screening form
ESRS-A
Extrapyramidal symptom rating scale – abbreviated 
version
EU
European Union
FDA
Food and Drug Administration
FSIQ
Full scale IQ scores
GABA
Gamma-aminobutyric acid
GABR
GABAA receptor subunit genes
GFR
Glomerular filtration rate
GLP
Good laboratory practice
GWAS
Genome-wide association studies
HBsAG
Hepatitis B surface antigen
HBcAb
Total hepatitis B core antibody
HCV
Hepatitis C virus
HDL
High-density lipoproteins
hERG
Human ether-a-go-go-related gene
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
IC50
Concentration values causing 50% inhibition
ICH
International Conference on Harmonisation
ICP
Idiopathic canine polyarteritis
IEC
Independent Ethics Committee
IMC
Internal Monitoring Committee
IMP
Investigational medicinal product
IND
Investigational new drug (application)
INR
International normalized ratio
IQ
Intelligence quotient
IRB
Institutional review board
IUD
Intrauterine device
IxRS
Interactive (voice/web) response system
LDH
Lactate dehydrogenase
LDL
Low-density lipoproteins
LPLO
Last patient, last observation
LSM
Least-squares mean
LTP
Long-term potentiation
MAD
Multiple-ascending doses


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
33/Protocol BP39207, Version 5
MATRICS
Measurement and treatment research to improve 
cognition in schizophrenia
MCCB
MATRICS consensus cognitive battery
MDD
Major depressive disorder
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed effect model for repeated measures
MTD
Maximal tolerated dose
MWM
Morris water maze
NAM
Negative allosteric modulator
NMDA
N-methyl-D-aspartate
NMDAR
NMDA receptor
NOAEL
No-observed-adverse-effect level
NOR
Novel object recognition
NOSIE
Nurses’ observation scale for in-patient evaluation
OTC
Over-the-counter
PAMs
Positive allosteric modulators
PANSS
Positive and negative syndrome scale
PBPK
Physiologically-based pharmacokinetic
PD
Pharmacodynamic
PI
Principal Investigator
PK
Pharmacokinetic
PR
Pulse rate
PRI
Perceptual reasoning index
PRN
Pro re nata, meaning ‘as needed’
PRO
Patient-reported outcome
PRS
Polygenic risk score
PSP
Personal and social performance scale
PSQI
Pittsburgh Sleep Quality Index
PT 
Prothrombin test
PTZ
Pentylenetetrazol
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia 
correction factor
QTcV
QT corrected for heart rate using van de Water’s 
formula
RBC
Red blood cell
RBR
Research biosample repository


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
34/Protocol BP39207, Version 5
RNA
Ribonucleic acid
RR
RR interval
SAD
Single-ascending dose
SAE
Serious adverse event
SAR
Serious adverse reaction
SBP
Systolic blood pressure
SCoRS
Schizophrenia cognition rating scale
SI
Système International d’Unités
SNP
Single nucleotide polymorphism
SoA
Schedule of Assessments
SOFAS
Social and Occupational Functioning Assessment 
Scale
SPA
Statistical programmer
SQLS
Schizophrenia quality of life scale
SUSAR
Suspected unexpected serious adverse reactions
TMT
Trail making test
ULN
Upper limit of normal
US
United States
V
Volume
VCI
Verbal comprehension index
VRFCAT
Virtual reality functional capacity assessment tool
WASI-II
Wechsler abbreviated scale of intelligence
WBC
White blood cell
WGS
Whole genome sequencing
WMS IV-LM
Wechsler memory scale - Fourth edition, Logical 
memory test
WMS IV-PAL
Wechsler memory scale - Fourth edition, Verbal paired 
associates
WoRQ
Work readiness questionnaire


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
35/Protocol BP39207, Version 5
1.
BACKGROUND AND RATIONALE
1.1
BACKGROUND ON DISEASE
Schizophrenia is a heritable condition characterized by psychotic, so-called positive 
symptoms, negative symptoms and cognitive deficits. Both negative symptoms and 
cognitive deficits are major determinants for functional outcome (Green 2000). Cognitive 
deficits are often present before onset of psychosis (Reichenberg et al 2010) and are not 
treated by antipsychotic drugs indicating that the dopaminergic abnormalities driving 
positive symptoms are not a factor underlying cognitive deficits (Keefe et al 1999, 
Minzenberg and Carter 2012). Therefore, there is a high need for effective treatments for 
cognitive deficits associated with schizophrenia. Key cognitive deficits in schizophrenia 
involve functions that are mediated by the hippocampus and prefrontal cortex such as 
learning, memory, executive functions and attention. Preclinical, imaging and recent 
human electrophysiological and functional imaging studies have demonstrated the 
interdependence of hippocampal and prefrontal abnormalities and alterations in 
hippocampal-prefrontal interactions in individuals with schizophrenia (Sigurdsson and 
Duvarci 2016).
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central 
nervous system. Numerous studies have consistently shown cortical GABAergic 
inhibitory circuits to play a pivotal role in regulating brain plasticity both during 
development and in adulthood. In primates, the maturation of cortical GABAergic 
circuitry extends into late adolescence and early adulthood, and thus, coincides with the 
vulnerable period for schizophrenia onset. It has therefore been argued that the 
neuropathology of schizophrenia may include abnormal post-natal development of the 
GABAergic systems and result in the emergence of symptoms during adolescence when 
the GABAergic system undergoes critical maturational changes (Lewis et al 2004). 
Indeed, dysfunction of GABA-mediated neurotransmission in schizophrenia is supported 
by post-mortem findings that included abnormalities in interneuron numbers, GABAA
receptor binding activity on pyramidal neurons and GAD67 expression (Benes et al 
2015). In addition, it has been postulated that these deficits converge on a common 
pathological mechanism that involves N-methyl-D-aspartate (NMDA) receptor 
hypofunction and oxidative stress (Hardingham and Do 2016). NMDA receptors are 
essential for several forms of synaptic plasticity and play a critical role in learning and 
memory (Paoletti et al 2013). One of the key models of the pathophysiology of 
schizophrenia in recent years has been the theory of NMDA receptor hypofunction –
postulating that deficient signaling through this receptor underlies key deficits and 
symptoms of schizophrenia, including cognitive impairments (Coyle 2012).
1.2
BACKGROUND ON BASMISANIL
Basmisanil (RO5186582) is a novel negative allosteric modulator (NAM) of GABA type A 
(GABAA) receptors which combines both binding and functional selectivity at the GABAA
5 subunit-containing receptors. At the time of writing, basmisanil is in clinical 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
36/Protocol BP39207, Version 5
development for the treatment of intellectual disability associated with Down syndrome 
(DS). Clinical development is also being initiated in stroke recovery and a Phase IIa 
study in stroke recovery patients is planned.
Among the different GABAA receptor subtypes, GABAA 5 subunit-containing receptors
are preferentially localized in the hippocampus and prefrontal cortex, key regions in the 
physiopathology of schizophrenia. This receptor subtype plays a key modulatory role in 
cognition (Collinson et al 2002, Crestani et al 2002). They are located at the base of 
dendritic spines of pyramidal cells and modulate excitatory glutamatergic input through 
the NMDA receptor (Möhler and Rudolph 2004). Thus, they modulate a key receptor 
involved in learning and memory which provides a mechanistic explanation on why 
GABAA 5 NAMs improve cognition in mice (Dawson et al 2006, Martinez-Cue et al 
2013), rats (Ballard et al 2009), non-human primates (Ballard et al 2009) and humans 
(Nutt et al 2007). As memory and learning are among the key functions deficient in 
schizophrenia, treatment with GABAA 5 NAMs can be expected to ameliorate these 
deficits.
In addition, consistent with the modulation of NMDA signaling by GABAA 5 receptor 
activity, GABAA 5 NAMs have been shown in recent studies to improve cognitive 
impairment in preclinical models of NMDA receptor (NMDAR) dysfunction. Specifically, a 
GABAA 5 NAM ameliorated deficits in the novel object recognition (NOR) test – a 
classical test of memory - and attentional set-shifting induced by subchronic and 
neonatal administration of phencyclidine in rats, respectively (Redrobe et al 2012). 
Moreover, other GABAA 5 NAMs attenuated MK-801 induced deficits in an incremental 
repeated acquisition task (Povroznik et al 2014), and in the NOR and Morris-Water Maze 
(MWM) tasks (Stamenic et al 2015). Therefore, the strong evidence for a key role of 
GABAA 5 receptors in cognitive functioning, particularly functions that depend on the 
integrity of hippocampal and prefrontal circuits, suggests that negative modulation of 
GABAA 5 receptors by GABAA 5 NAMs such as basmisanil may represent an effective 
treatment option for cognitive impairments associated with schizophrenia.
See the Basmisanil Investigator’s Brochure for further details on non-clinical and clinical 
studies.
1.2.1
Previous Non-Clinical Studies
1.2.1.1
Non-Clinical Pharmacology
In vitro, basmisanil was shown to be a potent NAM at the GABAA 532 receptor 
subtype with both binding and functional selectivity. Basmisanil exhibited more than 90-
fold binding selectivity for the human GABAA 5 receptor subtype compared to GABAA
1, 2, 3, 4, and 6 subunit containing receptors. In the Ts65Dn mouse model of 
Down syndrome which shows pronounced cognitive deficits, basmisanil rescued the 
deficit in Long-Term Potentiation (LTP) observed in hippocampal slices of these animals, 
demonstrating its ability to indirectly enhance NMDA receptor function.






RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
39/Protocol BP39207, Version 5
At the time of writing, basmisanil is currently being tested in a Phase II study in adults 
and adolescents with Down syndrome (BP27832; “CLEMATIS”) and a second study in 
children with Down syndrome aged 6-11 years (WP27860). 
1.2.2.1
Safety and Tolerability
The highest doses employed in the single-ascending dose (SAD) study (BP25129, 
1250 mg) and in the MAD studies (WP25366, 1000 mg BID; BP25543, 370 mg BID) did 
not reach the maximum tolerated dose (MTD). Across clinical studies, no adverse event 
(AE) pattern has emerged that would be regarded as characteristic of basmisanil. 
In the MAD study WP25366 and in the drug-drug interaction (DDI) study with 
itraconazole (WP29402), there was a signal for an initial, mild increase in heart rate and 
BP that became less apparent whilst dosing up to steady-state was continued. These 
cardiovascular observations were not reproduced in subjects with Down syndrome 
(BP25543); however, the data were too variable to exclude a possible cardiovascular 
effect. 
Prolongation of mean QTcF intervals was observed in Study WP29402 in which 
basmisanil 240 mg BID was co-administered with itraconazole resulting in a 4- to 5-fold 
increase in basmisanil plasma concentrations. No relevant AE pattern of basmisanil 
emerged in this study. A mean increase in heart-rate corrected QT interval using 
Fridericia’s formula (QTcF) of 4.5 and 9.5 milliseconds (ms) was seen around the time to 
maximum plasma concentration (Tmax) of basmisanil following 10 days of co-
administration of basmisanil 120 mg BID and 240 mg BID, respectively, with itraconazole. 
In subjects with normal hepatic clearance of basmisanil (e.g., in the absence of 
moderate or strong CYP3A4 inhibitors or absence of impaired liver function), no relevant 
increase in QTc can be assumed. 
Across clinical studies, increased serum creatinine concentrations were found with 
higher basmisanil doses. However, individual values typically remained within the 
standard reference range and changes were not judged to be clinically relevant. 
Furthermore, they were not associated with changes of other glomerular filtration rate 
(GFR) markers, i.e., iohexol clearance and cystatin C in serum. Thus, the elevations in 
serum creatinine are likely related to inhibitory effects of basmisanil on the tubular 
creatinine transporters as shown in vitro. Of note, the magnitude of the serum creatinine 
increase matches the fraction of creatinine clearance through tubular secretion and such 
increases returned to normal shortly after treatment stop.
Of note, non-selective GABAA 5 NAMs may be associated with side-effects related to 
interaction with GABAA 1, 2, and 3 receptors, such as convulsions, sleep problems 
or anxiety. In contrast, basmisanil is a highly selective GABAA 5 NAM and previous 
clinical trials did not reveal a basmisanil-related alert for such side-effects. In particular, 
electroencephalogram (EEG) monitoring did not reveal treatment emergent epileptiform 




RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
41/Protocol BP39207, Version 5
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
1.3.1
Study Rationale
Recent studies on the genetics of schizophrenia have established an important role for 
rare (less than 1% in frequency) and large (more than 100 kilobase) copy number 
variants (CNVs) in the etiology of this disorder (Malhotra & Sebat 2012). Among the 
susceptibility loci identified, the 15q11-13 duplication was found to confer high-risk for 
schizophrenia (Malhotra & Sebat 2012, Rees et al 2014). This is a complex locus that 
contains, amongst others, a cluster of three GABAA receptor subunit genes (GABR): 
GABRB3, GABRA5 and GABRG3 which encode GABAA receptor subunits 3, 5, and 
3, respectively. The duplication is believed to lead to an abnormal overexpression of the 
respective subunits. In addition, genetic variation across these particular GABR subunit 
genes has also been associated with schizophrenia risk (Huang et al 2014, Beneyto et al 
2011) and the severity of psychotic symptoms (Sun et al 2012, Bergen et al 2009) 
providing additional support for an involvement of abnormalities in these GABA subunits 
in the pathophysiology of schizophrenia.
As detailed above, GABAA 5 subunit-containing receptors are preferentially localized in 
the hippocampus and prefrontal cortex - key regions implicated in the physiopathology of 
schizophrenia and in particular, in cognitive deficits associated with schizophrenia. They 
are expressed at the base of dendritic spines of pyramidal cells allowing them to 
modulate excitatory glutamatergic input through the NMDA receptor (Möhler and 
Rudolph 2004). This provides a mechanistic explanation on why GABAA 5 NAMs 
improve cognition in rodents (Dawson et al 2006, Martinez-Cue 2013, Ballard et al 2009), 
non-human primates (Ballard et al 2009) and humans (Nutt et al 2007). 
As reviewed in more detail in Section 1.2, the assumed improvement of NMDA signaling 
by GABAA 5 NAMs can plausibly explain the amelioration of cognitive impairment in 
preclinical models of NMDAR dysfunction. Therefore, the strong evidence for a key role 
of GABAA 5 receptors in cognitive functioning, particularly functions that depend on the 
integrity of hippocampal and prefrontal circuits, suggests that negative modulation of 
GABAA 5 receptors by GABAA 5 NAMs such as basmisanil may represent an effective 
treatment option for cognitive impairments associated with schizophrenia.
1.3.2
Benefit-Risk Assessment
Overall, in all clinical studies, basmisanil has been found to be safe and well-tolerated at 
the doses used in this trial without relevant effects on laboratory parameters. A trend for 
longer QTcF intervals at concentrations higher than achieved with the dose selected for 
this study (240 mg BID per oral) was observed. However, no relevant QTcF prolongation 
can be assumed for concentrations generated with a 240 mg BID dosing regimen in 
subjects with normal hepatic clearance of basmisanil (e.g., in the absence of moderate 
or strong CYP3A4 inhibitors or absence of impaired liver function). Patients with 
schizophrenia may be receiving atypical antipsychotics which may prolong QTc although 
the magnitude among antipsychotic drugs varies. While it is not assumed that basmisanil 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
42/Protocol BP39207, Version 5
will act synergistically with such antipsychotics on QTc, QTc interval will be monitored at 
the initiation of basmisanil treatment to address this risk.
Results obtained in preclinical models of schizophrenia have led to the hypothesis that 
positive rather than negative modulators of the GABAA 5 receptor could be beneficial 
for control of positive symptoms of schizophrenia (Lodge and Grace 2011). Thus, a 
theoretical risk for GABAA 5 NAMs to worsen psychotic symptoms could be inferred. 
However, when basmisanil was tested in clinical trials, even at high doses, no 
pro-psychotic liability emerged from AE reporting. Initiation of basmisanil treatment 
during an in-patient stay allows the management and evaluation of this theoretical and 
small risk. 
Overall, the risk to patients with schizophrenia treated with basmisanil is considered 
small.
As outlined above, the unmet medical need for effective treatment for cognitive 
impairment associated with schizophrenia (CIAS) is enormous. Given the potential of 
basmisanil to significantly improve cognitive deficits in schizophrenia, the potential 
benefit to future patients, including those participating in this trial, would be significant. 
Thus, overall, the benefits outweigh the risks associated with basmisanil treatment. 
2.
OBJECTIVES
2.1
PRIMARY OBJECTIVES
The primary objective of this study is:

To investigate the efficacy of 24 weeks of basmisanil treatment on cognitive function 
as measured by the MATRICS consensus cognitive battery (MCCB) neurocognitive 
composite score, in stable patients with CIAS treated with antipsychotics.
2.2
SECONDARY OBJECTIVES
The secondary objectives for this study are as follows:
To evaluate the effect of 24 weeks of treatment with basmisanil in stable patients with 
CIAS treated with antipsychotics on the following:

Individual cognitive domains of the MCCB, namely attention, speed of processing, 
reasoning, working memory, visual learning, verbal learning and social cognition.

Additional specific hippocampal and prefrontal-dependent cognitive tasks and 
processes (as measured by the Trail making test [TMT]-B, Wechsler memory scale -
Fourth edition, verbal paired associates [WMS IV-PAL] and Wechsler memory scale 
- Fourth edition, logical memory test [WMS IV-LM]).

Functional capacity and performance (as measured by the Personal and Social 
Performance scale [PSP] and Schizophrenia Cognition Rating Scale [SCoRS]).


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
43/Protocol BP39207, Version 5

To evaluate the safety and tolerability of 24 weeks of basmisanil treatment in 
patients with CIAS treated with antipsychotics.

To characterize the steady-state pharmacokinetics (PK) of basmisanil and its 
metabolites, if appropriate, in stable patients with CIAS treated with antipsychotics 
using population PK modelling methods.
2.3
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To explore the effect of 24 weeks of treatment with basmisanil on semantic priming 
(measured in the category fluency test of the MCCB) and primacy/recency effects 
(measured in the Hopkins verbal learning test of the MCCB), two experimental 
measures of hippocampal-dependent cognitive processes.

To determine whether the patients’ genetic profile predicts effects of treatment with 
basmisanil on cognitive functions.

To evaluate the effect of 24 weeks of treatment with basmisanil on self-reported 
mood, sleep, subjective well-being and cognitive functioning (smartphone-based 
assessments).

To evaluate the effect of 24 weeks of treatment with basmisanil on functional 
capacity assessed by novel computerized measures and “work readiness”.

To evaluate the effect of 24 weeks of treatment with basmisanil on symptoms of 
schizophrenia including positive and negative symptoms.

To evaluate the effect of 24 weeks of treatment with basmisanil on quality of life.
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled, 
Phase IIb study, to evaluate the effects of 24 weeks of basmisanil treatment on CIAS in 
stable patients treated with antipsychotics. 
The final analysis will investigate the PK, safety and tolerability, and efficacy of 24 weeks 
of basmisanil treatment on cognition and functioning.
3.1.1
Overview of Study Design
Two doses of basmisanil (240 mg, 80 mg) will be tested against placebo. Approximately 
231 patients will be randomized to one of three treatment arms, in a 1:1:1 ratio:

Arm 1: 240 mg BID (may be lowered to 120 mg BID upon Safety Internal Monitoring 
Committee [IMC] decision, see Section 3.1.3).

Arm 2: 80 mg BID.

Arm 3: Placebo BID.


 
RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd 
44/Protocol BP39207, Version 5 
The sample size may be increased if the actual premature withdrawal rate is higher than 
expected. 
Randomization will be stratified based on age, sex and “schizophrenia cognitive 
subtype”. The stratification threshold for age will be  35 years and  35 years. The 
“schizophrenia cognitive subtype” will be determined at screening based on the 
difference between the pre-morbid intelligence quotient (IQ), estimated by the wide 
range assessment test (WRAT)-4 reading test standard score, and current full scale IQ 
scores (FSIQ), estimated by the Wechsler Abbreviated Scale of Intelligence – second 
edition (WASI-II) as shown on Figure 1 .  
Figure 1 Determination of the Schizophrenia Cognitive Subtype at 
Screening 
 
 
 
The study will be divided into 3 phases (Figure 2): 
 
A screening phase of approximately 5 weeks which includes Baseline 1 and 
Baseline 2 visits. 
 
A double-blind treatment phase with study drug of approximately 24 weeks. 
 
A follow-up phase of approximately 4 weeks after treatment discontinuation. 
 
Efficacy, safety, and PK assessments will be conducted throughout the study, as 
detailed in the Schedule of Assessments (Appendix 1). 
Patients will be treated until the end of the study treatment period, unacceptable 
toxicities, or withdrawal of consent. 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
45/Protocol BP39207, Version 5
Figure 2
Study Design
Screening
Study Drug Administration
Follow-up
5 weeks
24 weeks
4 weeks
The total duration of the study for each enrolled subject will be up to 34 weeks (from 
screening through completion of the last the last follow-up visit): 5-week Screening 
phase which includes a placebo test-phase, 24-week treatment period with study drug, 
and 4-week follow-up period.
As detailed in Section 1.3.2, a small theoretical risk may exist for basmisanil to worsen 
psychotic symptoms. For this reason, approximately the first 40 patients enrolled will be 
in-patients for the first week of treatment, and their safety and mental state will be 
closely monitored. Assessments to be performed during the in-patient stay are detailed 
in the Schedule of Assessments (Appendix 1), under the column “in-patients only”. 
Patients will be discharged on an individual basis at the Principal Investigator’s (PI’s) 
discretion, after a minimum of 7 days of treatment. The safety IMC will decide when 
newly enrolled patients can be started on study medication on an outpatient basis (see 
Section 3.1.3 for more details on the safety IMC). 
3.1.2
Stopping Rules
Pre-set stopping rules for individual study subjects are defined as follows: 

One of the following QTcF findings:
–
A QTcF value exceeding CTCAE ≥Grade 2 or >480 msec (when confirmed in repeat 
measurement within 30 minutes),
OR
–
A QTcF value exceeding a change from baseline of 60 msec (when confirmed in 
repeat measurement within 30 minutes).
If the QTcF does not normalize after discontinuation of the study drug and a 
washout period of 1 week, the patient should receive appropriate emergent 
treatment and be referred to a cardiologist for evaluation.

Any subject suspected of having seizure activity during the study, must receive 
appropriate emergent treatment, the study drug must be stopped, and the patient 
must be referred to a neurologist for evaluation (An episode of seizure not resolving 
within 3 minutes should be reported as an SAE).


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
46/Protocol BP39207, Version 5

Subjects with any elevated alanine aminotransferase (ALT)/elevated aspartate 
aminotransferase (AST) of 3upper limit of normal (ULN), and associated with an 
increase in bilirubin (2ULN) (i.e., a suspected “Hy’s law” indicating risk of
severe/serious liver impairment) in the absence of a different explanation. Such 
abnormalities should be followed by repeat testing within 48 to 72 hours and 
repeated two to three times weekly based on the patient’s clinical state. An 
evaluation by a hepatologist may be required if the abnormalities do not stabilize. All 
subjects with possible drug-induced liver injury should be followed until 
abnormalities return to normal even if the study drug has been discontinued.

Subjects who have creatinine increases above 1.5ULN that are confirmed on 
repeat testing within approximately 3 days.
3.1.3
Internal Monitoring Committees (IMCs)
This study will utilize a safety IMC and an efficacy IMC. All data analysis for the safety 
IMC and efficacy IMC reviews will be performed by the study statistician and the study 
statistical programming team.
3.1.3.1
Safety IMC
A Roche safety IMC will have safety oversight responsibility for the in-patient treatment 
part of this study. This safety IMC will consist of:

A clinical scientist, separate from the project team and who does not interact with 
the sites on a regular basis.

A clinical safety physician separate from the project team and who does not interact 
with the sites on a regular basis.

A clinical pharmacology leader who may be from the project team, but does not 
interact with the sites on a regular basis.

The study statistician.
The safety IMC will review and evaluate the unblinded safety data AEs, ECG, vital signs, 
global clinical condition and changes in symptomatology (and PK results if available), 
after 10, 25 and approximately 40 patients have reached one week of in-patient 
treatment. At any of these reviews of the safety data, the safety IMC will decide if further 
in-patient monitoring is needed for the subsequent patients enrolled or whether the study 
can be safely conducted with out-patient visits. Screening and enrollment should not be 
stopped. Participants who had started the in-patient period will remain as in-patient to 
finish the 1-week period. After patient 40, newly randomized subjects will participate as 
in-patients until the Sponsor indicates that sites are clear to randomize subjects as 
outpatients.
The safety IMC will specifically assess the changes from baseline in the ECG 
parameters (HR, QRS, QTcF), looking for a dose-response effect among cohorts or a 
correlation with exposure. 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
47/Protocol BP39207, Version 5
The AE profile as well as any evidence of emerging or worsening psychotic or other 
symptoms gleaned from validated instruments implemented (such as the positive and 
negative syndrome scale [PANSS] or the Nurse’s Observation Scale for In-patient 
Evaluation - 30 items Scale [NOSIE-30]) will be carefully examined across cohorts by 
the safety IMC.
The safety IMC will also review the concomitant anti-psychotic therapies for the enrolled 
patients looking for DDIs or safety concerns based on the AE profile, ECG parameters 
and vital signs. 
In case of clinically significant safety findings in the 240 mg cohort including a report of a 
Serious Adverse Reaction (SAR) attributable to basmisanil, QTcF values above 
480 msec or an increase of QTcF of60 msec from baseline, suspected seizure activity, 
or significant worsening of the underlying schizophrenia, the safety IMC can advise to 
stop enrolling in this cohort and to discontinue the patients in the 240 mg BID cohort 
from the study. In this case, a new dose arm of 120 mg BID will be opened. Patients who 
would have been newly randomized to the highest dose (240 mg BID) would from then 
on be randomized to 120 mg BID treatment. The safety IMC can reinstitute the in-patient
monitoring for patients randomized to 120 mg BID with reviews after 10, 25 and 40 
patients to ensure the safety of the 120 mg BID dose in the schizophrenia patient 
population treated on an out-patient basis. Additional details may be found in the Safety 
IMC Agreement Document.
All safety data obtained during outpatient treatment in this study will be reviewed 
throughout the study by the Sponsor in a treatment-blinded manner.
3.1.3.2
Efficacy IMC
Once approximately 90 patients have completed at least 12 weeks of treatment, an 
efficacy IMC (consisting of the members of the safety IMC along with the study 
translational medicine leader, a senior Roche clinical representative independent from 
the study team, a pharmacometrician, and others who will be involved in the decision-
making process as needed) will conduct an interim analysis for futility on the primary 
endpoint of the study. The committee will review and evaluate the data unblinded at the 
group level (including safety data and PK results if available), and the decision will be 
taken to either continue the study unchanged, to stop one arm or to end the study.
Descriptions of the conduct of the analysis, including pre-defined success criteria for the 
efficacy interim analysis, are summarized in Section 6.10 and will be described in further 
detail in a separate Efficacy IMC Agreement Document. 
3.1.4
End of Study
The end of the study is defined as the date when the Last Patient, Last Observation 
(LPLO) occurs. LPLO is expected to occur approximately 28 weeks after enrolment of 
the last patient.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
48/Protocol BP39207, Version 5
3.2
RATIONALE FOR STUDY DESIGN
This Phase IIb study is designed to provide initial safety and efficacy information of two 
doses of basmisanil against placebo, for the treatment of CIAS. The study is powered to 
detect an effect size of approximately 0.5. 
As the time-course of potential cognitive effects is unknown and may not follow the 
known trajectory of symptomatic improvement, a study duration of six months was 
chosen as it is assumed that six months will provide enough time for any potential 
cognitive and functional effects to emerge. 
3.2.1
Rationale for Dosage Selection
 
 These doses thus 
differentiate from one other and ensure that biologically relevant occupancy ranges are 
fully covered. 
In addition, in a recently completed study (BP27832; “CLEMATIS”) for the treatment of 
intellectual disability associated with Down syndrome, a dose of 240 mg BID for up to 
6 months in adults and adolescents was safe and well-tolerated.
3.2.2
Rationale for Study Population
This study will enroll stable male and female schizophrenic patients aged between 
18 and 50 years, who have been on stable antipsychotic treatment for at least 3 months.
Cognitive impairment is a prominent feature of schizophrenia, with more than 80% of 
patients exhibiting deficits. The pattern of cognitive deficits associated with 
schizophrenia does not significantly differ between males and females. Both sexes are 
hence eligible for this study. 
Multiple lines of evidence suggest that neuroplasticity and the capacity to learn are a 
function of age, which decrease in later adulthood. It is therefore hypothesized that the 
potential cognition-enhancing effects of basmisanil may be more readily detected in 
younger adults. As cognitive remediation therapies in the schizophrenic population have 
been shown to be most effective before the age of 50 years, the upper age limit of 
50 years has been selected for this study. 
3.2.3
Rationale for Biomarker Assessments
An individual’s genetic profile may predict response to GABAA 5 NAM treatment, 
providing the opportunity to better understand the pathophysiology of CIAS and to 
develop a treatment response stratifier. Specifically, single nucleotide polymorphisms 
(SNPs) have been identified which are both associated with an increased risk for 
schizophrenia (Purcell et al 2009) as well as enhanced plasticity, GABA- or 
glutamatergic functioning, and cognitive functioning (Ripke et al 2014), and in 
non-clinical populations, SNPs which are associated with enhanced hippocampal-


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
49/Protocol BP39207, Version 5
dependent episodic memory functioning (Debette et al 2015) and general cognitive 
functioning (Davies et al 2015, 2016). The genetic profile corresponding to these SNPs 
can be quantified with a polygenic risk score (PRS), which weighs each SNP’s allelic 
frequency with the respective genome-wide association studies (GWAS) odds ratio. 
Additionally, CNV of complement system C4A and C4B short and long forms have also 
been associated with an increased risk for schizophrenia and decreased hippocampal-
dependent cognitive functioning (Sekar et al 2016). This study will therefore collect blood 
for analyses with standard SNP arrays and digital droplet polymerase chain reaction to 
determine whether the PRS and C4 CNVs, respectively, predict treatment response 
(i.e., change in MCCB neurocognitive composite score and other outcome measures) to 
basmisanil.
3.3
OUTCOME MEASURES 
3.3.1
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature and severity of AEs.

Incidence, nature and severity of treatment discontinuations due to AEs.

Change from baseline in Systolic (SBP) and diastolic blood pressure (DBP) and 
pulse rate (PR).

The following ECG parameters will be obtained: HR, PQ (PR), QRS, QT, RR and 
QTcF along with information on T- and U-waves.

Changes in ECG parameters as compared to baseline ECG.

Incidence of clinically significant ECG abnormalities.

Incidence of laboratory abnormalities, based on hematology, clinical chemistry, and 
urinalysis test results:

Hematology: Hemoglobin, hematocrit, erythrocytes (RBC), platelets, leukocytes 
(WBC) differential (counts): neutrophils, eosinophils, lymphocytes, monocytes, 
basophils.

Blood chemistry: Aspartate aminotransferase (AST), ALT, total and conjugated 
bilirubin, ALP, albumin, creatinine, urea, total protein, total cholesterol, triglycerides, 
sodium, chloride, calcium, phosphate, potassium, glucose.

Urinalysis: protein, blood, glucose, leukocytes, nitrites and pH.

The Extrapyramidal Symptom Rating Scale – abbreviated version (ESRS-A).

The PANSS items comprising the positive symptoms and hostility/excitement factors 
(for in-patients only).

Suicidality assessed by the Columbia Suicide Severity Rating Scale (C-SSRS).

The Nurse’s Observation Scale for In-patient Evaluation - 30 items (NOSIE-30) (for 
in-patients only).


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
50/Protocol BP39207, Version 5
3.3.2
Pharmacokinetic (PK) Outcome Measures
The PK outcome measures are:

Population and individual primary PK parameters estimation (e.g., apparent 
clearances and volumes) and the influence of various covariates on these 
parameters.

Secondary PK parameters (e.g., AUC and Cmax) derived from the individual post-hoc 
predictions.
3.3.3
Efficacy Outcome Measures
The efficacy outcome measures for this study are:

MCCB neurocognitive composite score.

WMS IV-PAL score.

WMS IV-LM score.

TMT part B (TMT-B) and part A (TMT-A).

PSP scale.

SCoRS.

Clinical global impression – severity (CGI-S).

Clinical global impression – improvement (CGI-I).
3.3.4
Patient-Reported Outcome Measures
The patient-reported outcome measures for this study are as follows:

Schizophrenia Quality of Life Scale (SQLS).

Smartphone-based Likert scales evaluating mood, sleep, subjective well-being and 
cognitive functioning and treatment expectancy.
3.3.5
Exploratory Outcome Measures
The exploratory outcome measures for this study include but are not limited to the 
following:

Positive and Negative Syndrome Scale (PANSS).

Brief Negative Symptom Scale (BNSS).

The Category Fluency test of the MCCB (semantic priming).

The Hopkins Verbal Learning Test of the MCCB (primacy and recency effects).

Virtual Reality Functional Capacity Assessment Tool (VRFCAT).

University of Miami Computerized Functional Assessment System (CFAS).

The work readiness questionnaire (WoRQ).


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
51/Protocol BP39207, Version 5
4.
MATERIALS AND METHODS
4.1
CENTER
This is a multi-center study to be conducted in the US. An additional site(s) may be 
included for back-up purposes and may be activated if needed.
Administrative and Contact Information, and the List of Investigators are provided 
separately.
4.2
STUDY POPULATION
The study population consists of male and female subjects with schizophrenia aged 
18-50 years who are on stable antipsychotic therapy.
4.2.1
Recruitment Procedures 
Patients will be identified for potential recruitment using pre-screening enrollment logs, 
Institutional Review Board (IRB)-approved newspaper/radio advertisements, mailing lists 
and referral networks.
4.2.2
Inclusion Criteria
Patients must meet the following criteria for study entry:
1.
Male or female subjects aged between 18 and 50 years.
2.
Able to participate and willing to give written informed consent.
3.
Able to understand key risk and benefits of the study as demonstrated by a score 
10 on the Evaluation to Sign Consent (ESC) form.
4.
Able to perform study assessments and procedures and comply with the study 
protocol, including one week of hospitalization/in-patient stay.
5.
Diagnosis of schizophrenia of any type utilizing the Mini International 
Neuropsychiatric Interview (MINI) and Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition, (DSM-5) – direct clinical assessments, family informants 
and past medical records.
6.
Evidence of stability of symptoms for 3 months at screening, i.e., without 
hospitalizations for schizophrenia or increase in level of psychiatric care due to 
worsening of symptoms of schizophrenia.
7.
Schizophrenia clinical symptom severity defined by the following: Hallucinatory 
Behavior item score5 and a Delusion item score5 of the PANSS.
8.
On a stable regimen of antipsychotic therapy for at least 3 months at screening and 
receiving no more than two antipsychotics. Antipsychotic regimen: Patients must be 
on a "primary" antipsychotic and may be on a secondary antipsychotic. The amount 
of the secondary antipsychotic has to be equal to or less than the equivalent dose of 
the primary antipsychotic and the sum of the primary and secondary antipsychotics 
must be6 mg of risperidone equivalents (refer to Appendix 2 for conversion of 
antipsychotic doses to risperidone equivalents). 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
52/Protocol BP39207, Version 5
9.
Has an identified informant, considered reliable by the Investigator (or designee) to 
provide support to the patient to help ensure compliance with study treatment, study 
visits and protocol procedures. The informant should know the patient for at least 
3 months, see the patient outside of the clinical context on a weekly basis, and 
should be able to provide information on the patient helpful for completing study 
rating scales. The informant should be available for telephone interviews throughout 
the study and attend study visits when possible.
10. Fluent in English.
11. A body mass index (BMI) between 18 and 38 kg/m2 inclusive.
12. For women of childbearing potential: Use contraceptive methods (hormonal or 
non-hormonal) that result in a failure rate of1% per year during the treatment 
period and for at least 28 days after the last dose of study drug. 
Note: A woman is considered to be of childbearing potential if she is 
post-menarcheal, has not reached a post-menopausal state (12 continuous 
months of amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). Examples of 
contraceptive methods with a failure rate of1% per year include bilateral tubal 
ligation, male sterilization, established, proper use of hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
4.2.3
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from participation in the 
study:
1.
Pregnant or lactating.
2.
Current DSM-5 diagnosis other than schizophrenia including bipolar disorder, 
schizoaffective disorder and major depressive disorder (MDD).
3.
Clinically significant metabolic, hepatic, hematological, pulmonary, cardiovascular, 
gastrointestinal or urological disorder.
4.
Any history of diagnosed seizure disorder.
5.
Clinically significant neurological illness or significant head trauma that affects 
cognitive function, in the judgment of the PI.
6.
FSIQ 65 on the Wechsler Abbreviated Scale of Intelligence (WASI–II) at screening.
7.
Any clinically relevant ECG abnormalities at screening, including an average
triplicate QTcF above 450 msec.
8.
Clinically significant abnormal vital signs or laboratory test results at screening.
Specifically, for the clinical chemistry parameters: 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
53/Protocol BP39207, Version 5
o
the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
exceeding 2 fold the upper limit of normal (ULN) in combination with
the total bilirubin > ULN with the exception of Gilbert syndrome
o
serum creatinine exceeding 1.5-fold ULN. 
9.
Positive result at screening for hepatitis B (HBV), hepatitis C (HCV, untreated), or 
human immunodeficiency virus (HIV)-1 and -2. HCV patients who have been 
successfully treated and who test negative for HCV RNA, may be considered 
eligible for entry into the study. See Section 4.6.1.6 viral serology, laboratory 
assessments.
10. Concomitant use of prohibited medications (see Section 4.5.2). 
11. Moderate to severe substance use disorder (other than nicotine or caffeine), as 
defined by the DSM-5, within the last 12 months.
12. Confirmed positive test for alcohol or drugs of abuse at screening or at baseline.
13. Failure to detect blood concentrations of the prescribed antipsychotic medication. If
no commercial test is available for recently approved antipsychotics, the decision
will be taken on a case by case basis between the Investigator and the Roche TML 
(or designee).
14. Subjects with a history of poor compliance in the last 2 years.
15. Subjects who have experienced a change in their living situation in the last 3 months 
which would preclude the availability of a reliable informant (refer to Section 4.2.2).
16. Suicide attempt within one year or currently at risk of suicide in the opinion of the 
Investigator.  
17. Receipt of an investigational drug within 3 months prior to screening.
18. Any medical condition or other factors, as judged by the Investigator, which may 
interfere with the subjects’ participation or his/her ability to participate in this study.
19. A planned hospitalization during the time of the study (i.e., for elective surgery. Note: 
The one-week in-patient stay for the first approximately 40 patients is not 
exclusionary).
4.3
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Patients will be randomized to placebo, or one of the two active treatment doses (80 mg 
and 240 mg BID). Randomization will be stratified by sex, age, and cognitive subtype as 
described in Figure 1. The randomization numbers will be generated by the Sponsor or 
its designee. With the exceptions described below, the randomization list will not be 
available to the project team at Roche or to any personnel at the study centers.
The randomization list will be made available to the individual responsible for PK sample 
bioanalysis (and pharmacodynamics [PD] bioanalysis if appropriate). The list will also be 
provided to statisticians and programmers at Roche as needed to create unblinded data 
displays for the internal safety monitoring committee reviews and the efficacy interim 
analysis.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
54/Protocol BP39207, Version 5
Emergency Unblinding:
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected serious adverse events (SAEs; see Section 5.1) that are 
considered by the Investigator to be related to study drug.
The PIs will receive a set of sealed treatment codes. If the identity of the test medication 
needs to be known in order to manage the patient’s condition, the treatment code for 
that patient may be broken.
In the event of an emergency, the treatment code for an individual patient will be readily 
available to the Investigator and Sponsor through the interactive (voice/web) response 
system (IxRS).
All such occurrences should be documented in the study file. Treatment codes should 
not be broken except in emergency situations and, if possible, the responsible scientific 
leader should be contacted before the code is opened. At the final monitoring visit, the 
unused treatment codes will be counted and checked and a statement to the effect that 
all are intact (or not as the case may be) will be made by the monitor; this statement will 
be included or referred to in the final study report. All treatment codes will be returned to 
Roche.
Whenever disclosure of the identity of the test medication is necessary, adequate 
procedures will be in place to ensure integrity of the data. Any unblinding, at the 
investigating site end, will be documented in the study report with date, reason for 
identifying the drug and the name(s) of all the person(s) who had to be unblinded.
4.4
STUDY TREATMENT
4.4.1
Formulation, Packaging, and Handling
The study drug basmisanil will be provided in an immediate-release granule formulation 
packaged in sachets (“stick-packs”) containing 40 mg or 120 mg of basmisanil per 
sachet, two sachets to be administered orally twice daily. The placebo will be provided in 
a matching formulation, to be administered according to the same schedule as the study 
drug.
 
 
 Study drug packaging will 
be overseen by the Roche clinical trial supplies department and bear a label with the 
identification required by local law, the protocol number, drug identification and dosage. 
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
55/Protocol BP39207, Version 5
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature conditions,
and report any deviations or product complaints to the monitor upon discovery.
For further details, see the Basmisanil Investigator’s Brochure.
4.4.2
Dosage and Administration
The study medication is two stick-packs taken orally, twice daily (in the morning and in 
the evening within 30 minutes of a meal) over 24 weeks. Granules should be mixed with 
or sprinkled onto a small amount soft food (i.e., yogurt, apple sauce, or pudding) and all 
of the food consumed or as an alternative, patients have the option of placing the 
granules directly into their mouth followed by swallowing with a glass of water.
(Note: the granules must not be mixed with water before putting them into the mouth).
On Study Day 1, the first dose of medication will be administered in the hospital or at the 
clinic/study center once all pre-dose assessments have been conducted and eligibility 
has been confirmed. For all subsequent study visits, the morning dose will be taken at 
the study center. The last dose of medication will be the morning dose, administered at 
the clinic/study center at Week 24 visit.
Patients will be provided with a sufficient amount of medication to cover study treatment 
until the next site visit (including some overage). The qualified individual responsible for 
dispensing the study drug supply will prepare the correct medication supply required as 
instructed by IxRS and according to the randomization schedule. This individual will write 
the date dispensed and Patient Number on the study drug label and on the Drug 
Accountability Record. This individual will also record the study drug batch or lot number 
received by each subject during the study. 
Guidelines for treatment interruption or discontinuation are provided in Section 3.1.2 and 
Section 4.7.1.
4.4.3
Medication Adherence and Engagement Systems
4.4.3.1
Medication adherence system
The patient’s capacity to comply with taking twice daily study medication will be 
assessed during the screening period, between Baseline 1 and Baseline 2 visits. 
Patients will be asked to take placebo medication and to report each intake using a 
medication adherence monitoring platform (“Platform”) provided on a smartphone. A 
compliance report will be made available to support the PI’s assessment of the patient’s 
capacity to comply with the study requirements (refer to Section 4.2.2, “Inclusion 
Criteria”).
Patients will receive a medication reminder at a time within a pre-defined window to take 
their medication. Patients will follow a series of prescribed steps using the front-facing 
camera of the smartphone to confirm patient identity and medication to be taken. The 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
56/Protocol BP39207, Version 5
patient has to confirm ingestion of medication manually as well as the chosen dosing 
method (i.e., soft food vs. direct intake) as soon as the platform has been updated to 
include this functionality. In addition, built-in reminders and a communication system 
allows real-time intervention in case of non-compliance. Use of this Platform will in no 
way supersede or replace the physician and/or prescribed medication protocol. Because 
the Platform does not change the medication protocol, but rather encourages adherence, 
use of this Platform presents minimal risk to the patients.
After local determination by the Platform of proper medication administration, only data 
indicating whether or not the patient has properly taken the medication will be 
transferred to a secure centralized location. No video recordings or pictures identifying 
the patient will be stored on the smartphone nor transmitted to the server. The captured 
data is reviewable through a roles- and rules-restricted Health Insurance Portability and 
Accountability Act (HIPAA)-compliant system ensuring privacy of the information and 
only accessible to authorized personnel through two-way authentication.
Phone numbers of the patients will be collected and stored in an encrypted manner, 
allowing for direct communication to each patient from the system in an automated 
manner, or by study staff or other study monitoring personnel. Individuals not part of the 
study staff will not know the identity of study patients and will have no access to any 
medical or health records of the patients.
Patients who are found to regularly not take their medication will be contacted by study 
staff for retraining and motivational interventions.
4.4.3.2
Optional patient engagement system
Patients will also have the option to use a patient engagement application, referred to as 
a smartphone “App”.
The App is an optional service that patients can opt-in to use to remind them of 
activities/tasks relevant to study compliance, such as when to attend site visits. The App 
also provides supportive guides to help patients be aware of visit procedures, study 
information and instructions.
The App’s interactive features are intended to be a companion to the user during the 
course of a trial and include the following modules:

Study Information: targeted study information throughout the duration of the study.

Visit Schedule: site visit reminder as predefined in the Schedule of Assessments.

Goals: ability to implement study defined or personal goal targets (e.g., exercise, 
sleep, etc.).

Reminders: reminders for activities/task relevant to study compliance.  


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
57/Protocol BP39207, Version 5

Notes: journal functions for self-tracking information.
The App is available for down load to patients’ smartphone devices that support iOS and 
Android. The app will contain study-specific information only once activated by a patient. 
The study coordinator will provide the patient with a secure activation code, which they 
can use to activate the app upon their first use.
The App does not collect any patient identifiable information or clinical data. This app is 
intended for informational purposes only. It is not a substitute for professional medical 
advice. Patients should contact the study site Investigator or coordinator with any 
medical questions or concerns.
4.4.4
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study 
(basmisanil and placebo) will be provided by the Sponsor. The investigational site will 
acknowledge receipt of IMPs, to confirm the shipment condition and content. Any 
damaged shipments will be replaced.
The Investigator is responsible for the control of drugs under investigation. Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained. The Drug Dispensing Log must be kept 
current and should contain the following information:

The identification of the Patient to whom the study drug was dispensed (for example, 
patient initials and date of birth).

The date(s), quantity of the study drug dispensed to the Patient when out-patient.

The date(s) and quantity of the study drug returned by the Patient when out-patient.

All records and drug supplies must be available for inspection by the Roche Monitor 
[at every monitoring visit].
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
investigational medicinal product for safety reasons. In these cases, it may be 
acceptable for investigational study site staff to destroy dispensed investigational 
product before a monitoring inspection provided that source document verification is 
performed on the remaining inventory and reconciled against the documentation of 
quantity shipped, dispensed, returned, destroyed and provided that adequate storage 
and integrity of drug has been confirmed. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
58/Protocol BP39207, Version 5
Written documentation of destruction must contain the following:

Identity (e.g., MEDNO) of investigational product[s] destroyed.

Quantity of investigational product[s] destroyed.

Date of destruction.

Method of destruction.

Name and signature of responsible person [or company] who destroyed 
investigational product[s].
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.4.5
Post-Trial Access to Basmisanil
The Sponsor does not intend to provide basmisanil or other study interventions to 
patients after conclusion of the study or any earlier patient withdrawal.
4.5
CONCOMITANT THERAPY AND FOOD
4.5.1
Permitted Therapy 
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter 
(OTC) drugs, approved dietary and herbal supplements, nutritional supplements and any 
non-medication interventions (e.g., individual psychotherapy, cognitive behavioral 
therapy, smoking cessation therapy, and rehabilitative therapy) used by a patient from 
screening until the follow-up visit. All concomitant medications should be reported to the 
Investigator and recorded on the Concomitant Medications electronic Case Report Form 
(eCRF).
All medication administered to manage AEs (including extrapyramidal symptoms such as 
dyskinesia or akathisia) should also be recorded on the Adverse Event eCRF.
Allowed concomitant therapy, including medications used for the treatment of chronic 
medical conditions other than schizophrenia that are allowed, must be on a stable 
dosing regimen for 6 weeks prior to screening and remain stable throughout the study 
(from screening to last follow-up visit). Dose adjustments that are required as part of 
routine treatment to control the chronic condition (such as dose adjustments of insulin 
or anti-hypertensive medication) are permitted. Any changes in antipsychotic therapy, 
for management of worsening of symptoms or initiation of additional pharmacotherapy 
including antidepressant after randomization may be permitted on a case by case basis, 
in consultation between the PI and the Medical Monitor/Sponsor. The reason for such 
changes should be appropriately documented.




RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
60/Protocol BP39207, Version 5
–
GABAA PAMs must not be used within 12 hours of any cognitive assessment. 
At every visit when cognitive testing is scheduled as per Appendix 1, 
benzodiazepine intake will be evaluated by asking the patient about his 
consumption in the past week, and benzodiazepine blood levels will be 
measured (see Section 4.6.1.5).

GABA transaminase inhibitors (e.g., phenelzine, valproic acid and vigabatrin).

GABA reuptake inhibitors (e.g., tiagabine).

Other anxiolytics, hypnotics and sedatives (e.g., chloral hydrate, ethchlorvynol, 
meprobamate, methaqualone, paraldehyde). Low doses of trazodone or mirtazapine 
at night as ‘sleep aid pill’, or hydroxyzine, are allowed.

Anesthetics (e.g., chloroform, desflurane, etomidate, ketamine, propofol).

GABAA antagonists (e.g., flumazenil). Note: emergency use will require the subject 
to withdraw from the study.

GABA dietary supplements.

Other medications that could have a pharmacodynamic interaction with basmisanil:
gabapentin, pregabalin, lamotrigine, topiramate.
Modulators of CYP3A4 Activity
Basmisanil is predominantly cleared by metabolism via CYP3A4 and concomitant 
medications which significantly alter CYP3A4 activity will affect the PK of basmisanil. 
Following inhibition of CYP3A4 with itraconazole (study WP29402), the systemic 
exposure (146 g h/mL) and maximum plasma concentration (14.5 g/mL) of 240 mg 
BID basmisanil was 4.7- and 4.1-fold higher, respectively. This was associated with a 
maximum mean QTcF increase of 11.6 msec (90% CI: 5.3 to 17.9). These medications 
which are prohibited include:

Moderate or strong inhibitors of CYP3A4 (e.g., itraconazole, erythromycin, 
fluconazole, nefazodone, ritonavir, verapamil, grapefruit or grapefruit juice). 

Inducers of CYP3A4 (e.g., rifampicin, carbamazepine, pioglitazone, rifampin, 
modafinil, systemic glucocorticoids, St John’s Wort. (Please refer to Appendix 3 for 
a more detailed list of CYP3A4 inhibitors and inducers).
–
For inducers of CYP3A4, the washout window rule is to stop treatment 30 days 
or 5 half-lives prior to study drug administration, whichever is longer.
In case concomitant medications are needed that are moderate or strong CYP3A4 
inhibitors, the patient should be withdrawn from the study. 
Methods of administration which do not produce appreciable systemic drug exposure 
(e.g., topical administration for skin conditions) are permitted.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
61/Protocol BP39207, Version 5
 
 
Diphenhydramine
Diphenhydramine is not permitted because of potential cardiac effects.
Dofetilide
Dofetilide use is not permitted because of the potential for interaction between 
basmisanil and renally-cleared cationic drugs, as well as the very narrow therapeutic 
window of dofetilide. 
Anticholinergic medications
Anticholinergic (e.g. benztropine, biperiden, or trihexyphenidyl) are prohibited during the 
trial due to potential negative impact on cognition and the potential to interfere with the 
study primary endpoint. Anticholinergics prescribed as prophylaxis treatment for 
extrapyramidal symptoms need to be washed-out prior to enrollment. If deemed 
necessary by the PI, beta blockers (e.g. propranolol) can be prescribed instead.
4.6
STUDY ASSESSMENTS 
4.6.1
Description of Study Assessments
At each visit, assessments and examinations will be conducted as described in the 
Schedule of Assessments (Appendix 1).
The first approximately 40 eligible patients will be enrolled in the study as in-patients and 
will remain under supervision in the hospital for the first week of dosing. During this 
period, additional assessments will be conducted as described in the Schedule of 
Assessments (Appendix 1). 
4.6.1.1
Medical and Psychiatric History and Demographic Data
Medical history includes clinically significant diseases, prior medical interventions 
(e.g., surgeries), smoking/substance use history and prior functional status. All 
medication (e.g., prescription drugs, OTC drugs, herbal/homeopathic remedies, 
nutritional supplements) used by the patient within 5 weeks leading up to the screening 
visit will also be collected. Psychiatric history includes age at onset of illness, age at first 
hospitalizations, number of hospitalizations and date of most recent hospitalizations.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
62/Protocol BP39207, Version 5
Demographic data collected will include age, sex and race/ethnicity (as reported by the 
caregiver and where applicable). The number of years of education completed by the 
patient and by the parents will also be collected.
4.6.1.2
Physical Examinations
A general physical exam will be performed as outlined in the Schedule of Assessments 
(Appendix 1). 
Any abnormality identified should be recorded on the Medical History eCRF. Any new or 
worsened clinically significant abnormality should be reported as AEs on the Adverse 
Events eCRF. Height and weight will be recorded, and BMI will be calculated.
4.6.1.3
Vital Signs
Vital signs will include measurements of temperature, PR, and SBP and DBP while the 
patient is in a seated position after the patient has been resting for approximately 5 
minutes at each visit. Vital signs should be measured prior to blood draw or at least 10 
minutes after the last blood draw. When possible, the same arm should be used for all 
BP measurements.
BP, PR, and body temperature will be recorded at the time-points specified in the 
Schedule of Assessments (Appendix 1).
BP and PR measurements should be obtained in a quiet room at a comfortable
temperature, with the patient's arm unconstrained by clothing or other material. All 
measurements will be obtained from the same arm and, with the same cuff size, using a 
well-calibrated automatic instrument with a digital readout, throughout the study. 
4.6.1.4
Electrocardiograms
Triplicate ECG recordings (i.e., three useful ECGs without artifacts) will be obtained
within approximately 2-5 minutes at each specified time-point as listed in the Schedule of 
Assessments (Appendix 1). The average of the three readings will be used to determine 
ECG intervals (e.g., PR, QRS, QT). Whenever possible, the same brand/model of a 
standard high-quality, high-fidelity electrocardiograph machine equipped with computer-
based interval measurements should be used for each patient. The conditions should be 
as close as possible to pre-dose time-points; this includes but is not limited to food 
intake, activity level, stressors and room temperature.
To minimize variability, it is important that patients be in a resting position 
for 10 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate. Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording. ECGs should be performed prior to meals and 
any scheduled vital sign measurements and blood draws. In some cases, it may be


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
63/Protocol BP39207, Version 5
appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality.
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the patient’s 
permanent study file at the site. ECGs will be reviewed by a central laboratory.
ECG characteristics, including heart rate, QRS duration, and PR, and QT intervals, will 
be recorded on the eCRF. QTcB (Bazett’s correction), QTcF (Fridericia’s correction) and 
RR will be calculated by the Sponsor/recorded on the eCRF. Changes in T‑wave and 
U-wave morphology and overall ECG interpretation will be documented on the eCRF. 
T-wave information will be captured as normal or abnormal, U-wave information will be 
captured in two categories: absent/normal or abnormal.
4.6.1.5
Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. Laboratory safety tests shall be collected at time-points specified 
in the Schedule of Assessments (Appendix 1).
Additional samples may be taken at the discretion of the Investigator if the results of any 
test fall outside the reference ranges, or clinical symptoms necessitate additional testing 
to monitor patient’s safety. Where the clinical significance of abnormal lab results is 
considered uncertain, screening lab tests may be repeated before randomization to 
confirm eligibility. If there is an alternative explanation for a positive test for drugs of 
abuse, e.g., previous occasional intake of a medication or food-containing for example, 
codeine, benzodiazepines or opiates, the test could be repeated to confirm washout.
Furthermore, in case of a positive test for a drug of abuse at screening, that can be 
explained by a prescribed and permitted co-medication (see Section 4.5.1), a positive 
result at screening is not systematically exclusionary and will be evaluated on a case by 
case basis 
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the local or central laboratory.
Samples collected before dosing or from patients on placebo are to be taken as a 
precautionary measure and may not be analyzed in the first instance.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
64/Protocol BP39207, Version 5
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to the Sponsor for analysis. Instruction manuals and supply kits will be 
provided for all central laboratory assessments.

Hematology (leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential 
count [neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells]).

Serum chemistry (sodium, potassium, chloride, bicarbonate, glucose, urea, 
creatinine, protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, 
AST, urate, lactate dehydrogenase [LDH]).

Coagulation (international normalized ratio [INR], activated partial thromboplastin 
time [aPTT], prothrombin test [PT]).

Viral serology
o
HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, HIV-2 antibody).
Hepatitis B (surface antigen (HBsAg determines HBV positivity;
total hepatitis B core antibody (HBcAb) results do not contribute to 
eligibility assessment.)
o
Hepatitis C virus (HCV) antibody. In cases where hepatitis C was 
successfully treated, a positive HCV serology result can be followed by 
HCV RNA testing

Lipids (cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein 
[HDL] cholesterol, triglycerides).

Pregnancy test: All women of childbearing potential (including those who have had a 
tubal ligation) will have a blood or urine pregnancy test as outlined in the Schedule 
of Assessments (Appendix 1). 

Drug and alcohol screen:

Urine or saliva drug screen will be performed at time points indicated in Appendix 1. 
Agents tested for are at minimum: opiates, amphetamines, cocaine, hallucinogens, 
PCP, and cannabis and alcohol. An alcohol saliva test can be performed at any time 
during the study at the PIs discretion.

Benzodiazepine assessment: Benzodiazepine levels will be measured in blood 
samples as described in Appendix 1 (see Section 4.5.2 on use of GABAA PAMs). 
4.6.1.6
Pharmacokinetic Assessments
Samples for population PK will be collected on all randomized patients in this study. All 
patients entering the study will have blood samples taken as described in Appendix 1. All 
pre-dose samples should be scheduled to occur at a time which would not significantly 
delay the time a patient is regularly taking the study medication. Samples will be 
analyzed for basmisanil (and M1 and other metabolites, if relevant).
4.6.1.7
Genotyping and Biomarker Assessments
Two whole blood samples will be collected for (1) Research Biosample Repository (RBR) 
long-term storage for e.g., future genotyping for consortia contributions (Section 4.6.1.9) 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
65/Protocol BP39207, Version 5
and (2) DNA extraction for genotyping those genes associated with cognition, brain 
plasticity, and GABA- and glutamatergic functioning, as well as the complement C4 
CNVs.
4.6.1.8
Disease-Specific Assessments
Mini International Neuropsychiatric Interview
The Mini International Neuropsychiatric Interview (MINI) (Sheehan 1998) is a structured 
diagnostic interview designed to meet the need for a short but accurate structured 
psychiatric interview for multicenter clinical trials. It is a method of organizing a 
psychiatric interview to make sure all relevant diagnoses are considered. The MINI has 
been validated against the Structured Clinical Interview for DSM diagnoses. The 
interview with the patient will be conducted by a trained psychiatrist. Administration time 
is approximately 20 minutes. 
Wide Range Achievement Test 4 (WRAT-4) – Reading Test
The WRAT-4 (Wilkinson et al 2006) reading test measures basic reading skills. The test 
covers ages from 5 to 75 years old and takes approximately 15-30 minutes to administer. 
WRAT-reading test will be administered according to standard instructions, at screening 
only. The age-corrected standard score obtained will be used as pre-morbid IQ estimate.
The WRAT-4 test will be audio- and video-recorded at Screening Visit for quality control 
purposes. The patient’s face will not be visible on the recordings. 
Wechsler Abbreviated Scale of Intelligence – Second Edition (WASI-II) 
The WASI-II is an intelligence test designed to estimate IQ in individuals aged 6 to 90 
years (Wechsler 2011). The FSIQ score of the four-subtest form will be derived based 
on the total combined performance on the Vocabulary, Similarities, Block Design and 
Matrix Reasoning subtests. A Verbal Comprehension Index (VCI) (Vocabulary and 
Similarities subtests) and a Perceptual Reasoning Index (PRI) (Block Design, Matrix 
Reasoning subtests) will also be derived. The WASI-II four subtest form should take 
approximately 30 minutes to administer.
MATRICS Consensus Cognitive Battery (MCCB)
The MATRICS initiative has established a regulatory pathway for the use of the MCCB
as cognitive outcome measure in CIAS clinical trials. This comprehensive cognitive 
battery provides a relatively brief evaluation of cognitive domains relevant to 
schizophrenia and related disorders (Nuechterlein et al 2008). It was designed to 
measure seven cognitive domains:

Speed of processing: Brief Assessment of Cognition in Schizophrenia (BACS) 
symbol-coding; TMT-A; Category Fluency: animal naming.

Attention/vigilance: Continuous Performance Test (including identical pairs).

Working Memory: Spatial Span, Letter Number Span.

Verbal learning and memory: Hopkins Verbal Learning Test -Revised.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
66/Protocol BP39207, Version 5

Visual learning and memory: Brief Visuospatial Memory Test.

Reasoning and problem solving: Maze Test.

Social cognition: Emotional Intelligence Test.
Composite scores for each cognitive domain described above, as well as the 
neurocognitive composite score, which includes all but the social cognition domain, will 
be derived. The MCCB takes between 60 and 90 minutes to complete.
A clear practice effect has been reported in the literature for the MCCB, therefore the 
test will be administered twice prior to the formal baseline. In addition, previous exposure 
to the test will also be recorded (i.e. “has the MCCB ever been administered to the 
subject before?”, “if yes, how many times and date of last administration”).
The MCCB testing will be audio- and video-recorded at each visit for quality control 
purposes and for the purpose of obtaining measures of semantic priming (see Semantic 
Priming below). Of note, the patient will not be visible on the recordings. 
The time of the MCCB testing should as far as possible remain the same throughout the 
study visits (i.e. +/- 30 minutes around the time recorded at the baseline 1 visit), 
preferably before the lunch meal.
Primacy and Recency Region Effects in Episodic Memory
For the Hopkins Verbal Learning Test – Revised (see MCCB), the number of correctly 
recalled words in the immediate condition from the primacy (initial 25% of items) and 
recency (last 25% of items) regions will be noted and supplied to the Sponsor for 
analyses of learning and recall performance from the primacy and recency regions. 
Semantic Priming
Audio recording of the category fluency test (see MCCB), Category Fluency: Animal 
Naming will be provided to the Sponsor for semantic fluency analysis of consecutively 
produced words.
Trail Making Test (TMT)
The TMT consists of two parts: Trail making Part A, which is a part of the standard 
MCCB and Trail making Part B additionally included in this study. Circles containing 
numbers (Part A) or both numbers and letters (Part B) must be sequentially connected. 
The total score is the time spent to complete each part. TMT-A involves attention, visual 
search, motor functioning, and working memory and TMT-B additionally involves 
executive function. The difference (ratio) in performance between Part A and Part B 
reflects executive processes and will be used to assess executive functioning including 
cognitive set shifting abilities. This test should take 5 minutes to complete.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
67/Protocol BP39207, Version 5
Wechsler Memory Scale - Fourth Edition, Verbal Paired Associates (WMS 
IV-PAL)
The paired associates learning (I and II) of the WMS-IV (Wechsler 2009) is a test of 
verbal learning and memory that requires the subject to learn novel word pairs. The 
subject learns the word pairs across learning trials and is asked to recall them 
immediately (PAL I) or after a 30-minute delay (PAL II). This test should take 
approximately 10 minutes to complete.
Wechsler Memory Scale - Fourth Edition, Logical Memory Test (WMS IV-LM)  
Logical memory (LM) assesses narrative memory under free-recall conditions. Two 
short stories are presented orally. The examinee is asked to retell each story from 
memory immediately after hearing it (LM I). In the delayed condition (LM II), the 
examinee is asked to retell both stories from the immediate condition (delayed free 
recall). Each story contains 25 scorable units of information. Different stories will be used 
across visits: both WMS-IV LM stories will be presented at screening, while 2 different 
Sullivan LM (2005) stories will be administered at each of the following LM visits (i.e. 
baseline, week 12 and week 24). This test takes approximately 10 minutes to complete.
Clinical Global Impression – Severity (CGI-S) and Improvement (CGI-I)
The CGI (Guy 1976) is one of the most commonly used outcome measures in 
psychopharmacology clinical trials. The CGI is the general name for two scales: the CGI-
Severity scale (CGI-S), which measures global severity of illness at a given point in time 
and the CGI improvement scale (CGI-I), which measures change from the baseline state 
at following visits. The CGI rating scale permits a global evaluation by the clinician of the 
subject’s improvement over time. The CGI-S is a 7-point scale ranging from 1 (no 
symptoms) to 7 (very severe). The CGI-I is a seven-point scale, ranging from 1 (very 
much improved) to 7 (very much worse).
Personal and Social Performance scale (PSP)
The PSP (Morosini et al 2000) is a scale developed on the basis of the social functioning 
component of the DSM-IV Social and Occupational Functioning Assessment Scale 
(SOFAS). The PSP is a 100-point, single-item rating scale subdivided into 10 equal 
intervals. The ratings are based upon assessment of the subject’s functioning four main 
areas: 1) socially useful activities; 2) personal and social relationships; 3) self-care; and 
4) disturbing and aggressive behaviors.
Virtual Reality Functional Capacity Assessment Tool (VRFCAT)
The VRFCAT (Ruse et al 2014, Keefe et al 2016) is a virtual reality shopping trip 
performed on a windows computer. Prior to the performance of the task, a brief tutorial 
version of the VRFCAT, including a mouse usage tutorial administered with a short 
recipe. This tutorial (15 min) needs to be administered to all participants, regardless of 
their statements regarding computer familiarity. The task has several linked and 
sequential scenarios, including matching a recipe to the content of kitchen cabinets, 
preparing a shopping list, taking the correct bus, shopping efficiently, and catching the


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
68/Protocol BP39207, Version 5
correct return bus. These tasks are performed in a fixed sequence. Multiple forms of the 
VRFCAT exist; two versions (1 or 4) will be administered alternatively. All data are 
collected by the computer.
Once the task is launched, it operates itself continuously until the end of the procedure. 
As with all computerized assessments, the tester will be required to remain vigilant in 
order to ensure that the participant is continuously engaged in the task. This test should 
take approximately 30 minutes to complete.
University of Miami Computerized Functional Assessment System (CFAS)
The CFAS consists of four computerized simulations administered on a Windows PC. 
These simulations include ATM Banking, Telephone Voice Prescription Refill, Transit 
Ticket Purchase, and Doctors Visit. Data are collected automatically by the computer 
and are uploaded manually after each visit. At each testing session, a demographic 
information collection process takes place. Once each task is launched, there is no more 
input from the tester unless the task needs to be interrupted.
ATM Task: In this task, the participant engages in a series of banking transactions, 
including enter a PIN, choosing a language, checking balances, transferring money, and 
withdrawals. The task administers the banking tasks in a fixed order and the task ends 
itself when the participant reaches the end.
Refill Task: In this task, the participant uses a telephone keypad to access a voice menu 
to refill two prescriptions. The participant is asked to select a language, enter the 
prescription number, and choose a time for pickup. The process is repeated for the 
second prescription.
Transit Ticket Purchase: In this task, the participant uses a ticket kiosk to make a series 
of purchases in responses to situational requirements. The individual is asked to 
purchase single and multi-day tickets and to reload a fare card. Each of these task 
requirements is presented on the computer screen and the participant makes response 
selections following those instructions.
Doctor’s Visit: In this task, a simulated doctor’s visit occurs with five prescriptions being 
provided to the participant. The participant then is asked a series of questions about the 
prescriptions. They then are presented with a package insert for a new medication and 
asked questions about it. Next, they are asked to prepare a day’s worth of pills in a 
medication organizer. The task ends with the doctor providing information about the next 
visit and querying the participant regarding the requirements for that visit.
All subjects are expected to attempt all aspects of the tasks. For participants who claim 
no experience, the task serves as a problem-solving and skills-learning exercise.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
69/Protocol BP39207, Version 5
Note that the CFAS should be administered after the VRFCAT, because the VRFCAT 
has a mouse-use tutorial. The familiarity questionnaire should be completed in all cases, 
including reported familiarity with each task in the real world as well as experience with 
computers. The CFAS should take approximately 15 minutes to complete.
Work Readiness Questionnaire (WoRQ)
The WoRQ v4.0 (Potkin et al 2016) captures the patient’s capacity to initiate and 
maintain useful activity that could merit pay – or work readiness – as evaluated by the 
patient’s ability to conduct daily activities, interact with others and adhere to treatment, 
as well as on others’ perceptions of patient appearance, behavior, and impulse control. 
The questionnaire is composed of 7 items graded “strongly agree,” “agree,” “disagree,” 
or “strongly disagree,” to be completed using progress notes, medical records and input 
from informants, leading to a final dichotomous work readiness judgment, independent 
of current work status. The WoRQ requires an average completion time of < 5 minutes.
Schizophrenia Cognition Rating Scale (SCoRS)
The SCoRS (Keefe et al 2015) is an interview-based 20-item rating scale of daily 
functioning related to cognitive impairment that involves both patients and informants. 
Each item is rated on a 4-point scale. The SCoRS comprises an assessment of cognitive 
functioning based on the opinions of the patient and an informant, and an interviewer’s 
decisions about which source of information is more reliable for each item and the global
rating (1-10). SCoRS total scores have been shown to be strongly correlated with 
cognitive performance, functional outcome, and functional capacity in stable patients 
with schizophrenia. The SCoRS should take approximately 20 minutes to administer.
Brief Negative Symptom Scale (BNSS)
The BNSS (Strauss et al 2012) is a 13-item instrument designed for clinical trials that 
measures the severity of negative symptoms in 5 domains (subscales): blunted affect, 
alogia, asociality, anhedonia, and avolition. All ratings are based on a semi-structured 
interview with prompts and queries. Items are rated on a 7-point (0-6) scale, with anchor 
points ranging from the symptom being absent (0) to severe (6). Subscale scores as well 
as a total score will be derived. This test should take approximately 10-15 minutes to 
complete.
Positive and Negative Syndrome Scale (PANSS)
The PANSS is a 30-item rating scale which evaluates positive, negative and other 
symptoms in patients with schizophrenia (Kay et al 1987). The Positive Scale assesses 
the features exhibited in schizophrenia that are not present in those with a normal 
mental state. The Negative Scale assesses features that are absent in schizophrenia but 
that would be present in those with a normal mental state. Other sub-scales assess 
other aspects of schizophrenia including the overall severity of the disorder and the risk 
of aggression. Each item is rated on a 7-point scale (1absent, 7extreme). A total 
score as well as subscale and factor scores will be derived. It takes approximately 40 
minutes to administer.


 
RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd 
70/Protocol BP39207, Version 5 
During in-patient stay, items comprising the “Hostility/Excitement” and “Positive 
symptoms” factors as defined by Marder (Marder and Chouinard 1997), will be 
administered (Table 1 ): 
Table 1 
Items comprising the “Positive symptoms” and 
Excitement/Hostility” Marder factors 
 
Positive symptoms 
factor (8 items) 
  
P1 
Delusions 
P3 
Hallucinatory Behavior 
P5 
Grandiosity 
P6 
Suspiciousness 
N7 
Stereotyped thinking 
G1 
Somatic concern 
G9 
Unusual thought content 
G12 
Lack of judgement and insight 
 
 
 
Excitement/Hostility 
factor (4 items) 
P4 
Excitement 
P7 
Hostility 
G8 
Uncooperativeness 
G14 
Poor Impulse Control 
 
The Schizophrenia Quality of Life Scale - Revision 4 (SQLS-R4) 
The SQLS is a schizophrenia-specific quality of life self-report questionnaire (Wilkinson 
et al 2000). It is intended to assess the psychosocial level (e.g., depressive mood, lack 
of social interactions etc.)  and vitality level (e.g., lack of energy, tiredness, poor memory 
etc.) of patients with schizophrenia. The SQLS-R4 (Martin & Allan 2007) is the 4th 
revision made to the SQLS to improve its psychometric properties. It contains 33 items 
covering two domains: psychosocial (20 items) and vitality (13 items), scored using a 
Likert-type format. It takes 5-10 minutes to complete. 
Nurses’ Observation Scale for In-patients Evaluation (NOSIE-30) 
The NOSIE-30 (Honigfeld et al 1966) is a sensitive ward behavior rating scale, designed 
to assess the behavior of patients on an in-patient unit and is an accurate means of 
systematically assessing patient status and change from baseline in a clinical trial setting. 
The scale is rated based on continuous observation, according to the frequency of 
occurrence of 30 designated behaviours. Six factor scores are obtained: Social 
Competence, Social Interest, Personal Neatness, Irritability, Manifest Psychosis, and 
Retardation as well as a composite score. This scale will be administered by nurses to 
in-patients only. 
Extrapyramidal Symptoms Evaluation (ESRS-A) 
The presence and severity of extrapyramidal symptoms (EPS) will be evaluated using 
the ESRS-A (Chouinard et al 2005). The ESRS-A is a 28-item scale, designed to 
objectively and comprehensively measure EPS. The ratings will be made through a 
combination of a clinical interview, as well as motor examination by a trained research 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
71/Protocol BP39207, Version 5
physician or research psychologist. The time required to complete this assessment is 
approximately 10 minutes. 
Columbia Suicide Severity Rating Scale (C-SSRS)
The assessment of suicidality will be collected for all patients using the C-SSRS (Posner 
et al 2011). The C-SSRS is a tool used to assess the lifetime suicidality of a patient 
(C-SSRS baseline version, to be administered at screening) as well as any new 
instances of suicidality (C-SSRS since last visit version, at other visits as indicated in 
Appendix 1). The C-SSRS incorporates a structured interview to prompt recollection of 
suicidal ideation, including the intensity of the ideation, behavior and attempts with 
actual/potential lethality.
Smartphone Likert Scale Assessments
Three Likert scales assessing mood, quality of sleep, subjective well-being and cognitive 
functioning and treatment expectancy will be administered via an android smartphone. 
Patients will be instructed to fill in the Likert scales at defined time points during the trial.
4.6.1.9
Samples for Research Biosample Repository (RBR)
Overview of the RBR
The Roche RBR is a centrally administered group of facilities for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage and analysis of these 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.
Specimens will be collected from patients who give specific consent to participate in this 
optional RBR. Collected specimens will be used to achieve the following objectives:

To study the association of biomarkers with efficacy, AEs, or disease 
progression.

To increase knowledge and understanding of disease biology.

To study drug response, including drug effects and the processes of drug 
absorption and disposition.

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays.
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RBR is contingent upon the review and approval of the exploratory 
research and the RBR portion of the Informed Consent Form by each site's IRB or Ethics 
Committee (EC) and, if applicable, an appropriate regulatory body. If a site has not been 
granted approval for RBR sampling, this section of the protocol will not be applicable at 
that site.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
72/Protocol BP39207, Version 5
Sample Collection
One whole blood sample will be collected for RBR long-term storage, which may be 
used e.g., for future genotyping for consortia contributions.
The samples collected for DNA extraction may be used for whole genome sequencing 
(WGS) and other genetic analysis and may be sent to one or more laboratories for 
analysis.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this study but will also be explored in 
aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents.
For all samples, dates of consent and specimen collection should be recorded on the 
associated RBR page of the eCRF. For sampling procedures, storage conditions, and 
shipment instructions, see the separate laboratory manual.
RBR specimens will be stored and used until no longer needed or until they are 
exhausted. The RBR storage period will be in accordance with the IRB/EC‑approved 
Informed Consent Form and applicable laws (e.g., Health Authority requirements).
The repository specimens will be subject to the confidentiality standards (as described 
under Confidentiality in Section 8.4).
Confidentiality
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche Monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RBR specimens is confidential and may only 
be disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RBR specimen analysis on individual patients will generally not be 
provided to study Investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication.
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Patients will not be identified by 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
73/Protocol BP39207, Version 5
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or patients unless required by law.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR specimen data will become and remain the exclusive and 
unburdened property of Roche, except where agreed otherwise.
Consent to Participate in the RBR
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The Investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR. Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period. A separate, specific signature will be 
required to document a patient’s agreement to provide optional RBR specimens. 
Patients who decline to participate will not provide a separate signature.
The Investigator should document whether or not the patient has given consent to 
participate by completing the RBR Sample Informed Consent eCRF.
In the event of death or loss of competence of a subject who is participating in the 
Research, the participant's specimens and data will continue to be used as part of the 
RBR.
Withdrawal from the RBR
Patients who give consent to provide specimens for the RBR have the right to withdraw 
their specimens at any time for any reason. If a patient wishes to withdraw consent to 
the testing of his or her specimens, the Investigator must inform the Medical Monitor in 
writing of the patient’s wishes using the RBR Withdrawal Form and, if the trial is ongoing, 
must enter the date of withdrawal on the RBR Withdrawal of Informed Consent eCRF. 
The patient will be provided with instructions on how to withdraw consent after the trial is 
closed. A patient's withdrawal from Study BP39207 does not, by itself, constitute 
withdrawal of specimens from the RBR. Likewise, a patient’s withdrawal from the RBR 
does not constitute withdrawal from Study BP39207. Data already generated before time 
of withdrawal of consent to RBR will still be used.
Monitoring and Oversight
Specimens collected for the RBR will be tracked in a manner consistent with Good 
Clinical Practice by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form. Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in RBR for the purposes of 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
74/Protocol BP39207, Version 5
verifying the data provided to Roche. The site will permit monitoring, audits, IRB/EC 
review, and Health Authority inspections by providing direct access to source data and 
documents related to the samples.
4.6.2
Timing of Study Assessments
4.6.2.1
Order of Assessments 
Cognitive testing
The cognitive testing should be performed at a similar time of day and in the same 
sequence across all study visits, starting with the MCCB, including the TMT-B, at 
approximately 11 AM30 min.
Computerized assessments
Computerized assessments should be performed after the cognitive testing, and the 
VRFCAT should be performed before the CFAS.
All examinations will be performed according to the Schedule of Assessments as 
outlined in Appendix 1.
4.6.2.2
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
An Evaluation to Sign Consent (ESC) form will be used to ensure patients' 
understanding of the study. The form consists of 6 questions rated on a 0 to 2 scale for 
the level of understanding and participants are required to score at least 10 out of a 
possible 12 in order to participate in the study. It may be necessary to review the 
consent documents with the patient multiple times and repeat the ESC to ensure this 
degree of comprehension (maximum of 3 times). 
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that patients meet all eligibility criteria. The Investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons
for screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
Rescreening may be allowed once and only after approval by the Translational Medicine 
Leader or designee. 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
75/Protocol BP39207, Version 5
4.6.2.3
Assessments during Treatment
Under no circumstances will patients who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and 
re-enroll in the study.
All assessments must be performed according to the Schedule of Assessments 
(Appendix 1). Assessments scheduled on the day of study treatment administration 
should be performed prior to administration of study treatment, unless otherwise noted in 
the Schedule of Assessments. 
4.6.2.4
Early Termination Assessments
If a patient is discontinued from the study early, or in case of early study or site 
termination decided by the Sponsor, patients will be asked to return to the clinic to 
complete the FU visit 2, as per Appendix 1, 4 weeks after the last dose of study drug. 
4.6.2.5
Follow-Up Assessments
After the study completion/early termination visit, AEs should be followed as outlined in 
Sections 5.4.3 and 5.6.
4.7
PATIENT, STUDY, AND SITE DISCONTINUATION
4.7.1
Patient Discontinuation
The Investigator has the right to discontinue a patient from basmisanil or withdraw a 
patient from the study at any time. In addition, patients have the right to voluntarily 
withdraw from the study at any time for any reason. Reasons for discontinuation of study 
drug or withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time.

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study.

Investigator or Sponsor determines it is in the best interest of the patient.

Patient non-compliance.
Patients who fulfill the criteria described in the Stopping Rules (as defined in Section 
3.1.2) should be discontinued from the study.
For patients who exhibit a worsening of their underlying medical condition that can be 
managed on an out-patient basis with adjustment of their background medication, the 
decision to continue with the study will be made on a case-by-case basis in close 
consultation between the Investigator, the Medical Monitor, and the Sponsor. A 
worsening of symptoms of schizophrenia does not necessarily constitute a reason for 
withdrawal of the subject from the study. Appropriate changes in antipsychotic or other 
pharmacological (i.e., antidepressants) treatment can be instituted if discussed with and 
agreed to by the Medical Monitor/Sponsor, and should be recorded in the treatment 
section of the AE eCRF form.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
76/Protocol BP39207, Version 5
A hospitalization of the patient does not necessarily constitute a reason for withdrawal of 
the subject from the study (for instance, a short hospitalization for psychosocial reasons 
may be acceptable). Each case should be discussed with the Medical Monitor/Sponsor. 
It should be determined if the patient can continue the study medication while 
hospitalized. In case study medication cannot be continued while the patient is 
hospitalized, it should be determined if the hospitalization is of such duration that a 
continuation in the study after discharge can be justified. The decision should be 
recorded in the eCRF.
4.7.1.1
Discontinuation from Study Drug
Patient must discontinue study drug if they experience any of the following:

Pregnancy.

Cardiovascular events, suspected seizure activity, liver abnormalities, 
creatinine increases as described in Section 3.1.2.

Patient unable to continue to comply with study requirements.

Unblinding of a patient.
Patients who discontinue study drug prematurely will be asked to return to the clinic for a 
study completion/early termination visit (see Section 4.6.2.4). The primary reason for 
premature study drug discontinuation should be documented on the appropriate eCRF. 
Patients who discontinue study drug prematurely will not be replaced.
4.7.1.2
Withdrawal from Study
Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.
Patients will not be followed for any reason after consent has been withdrawn.
4.7.2
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of AEs in this or other studies indicates a potential 
health hazard to patients.

Patient enrollment is unsatisfactory.

Important new information becomes available that may be relevant to the 
subject’s consent.
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
77/Protocol BP39207, Version 5
The Sponsor has the right to replace a site at any time. Reasons for replacing a site may 
include, but are not limited to, the following:

Excessively slow recruitment.

Poor protocol adherence.

Inaccurate or incomplete data recording.

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice.
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording the incidence, nature and 
severity of AEs, including SAEs and non-serious AEs of special interest; measurement 
of protocol‑specified safety laboratory assessments; measurement of protocol-specified 
vital signs, ECGs and laboratory parameters; and other protocol-specified tests 
described in Section 5.1.1.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.1.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution. An AE can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9.

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline.

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X‑ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug.

AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies).


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
78/Protocol BP39207, Version 5
5.1.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A SAE is any adverse event that meets any of the following criteria:

Fatal (i.e., the AE actually causes or leads to death).

Life-threatening (i.e., the AE, in the view of the Investigator, places the patient 
at immediate risk of death). This does not include any AE that, had it occurred in a more 
severe form or was allowed to continue, might have caused death.

Requires or prolongs in-patient hospitalization (see Section 5.3.5.11).

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions).

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug.

Significant medical event in the Investigator's judgment (e.g., may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above).
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an AE (rated as mild, moderate, or severe, or according to a pre-defined grading criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF.
SAEs are required to be reported by the Investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions).
5.1.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)

Non-serious AEs of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions). Also see Section 3.1.2, Stopping 
Rules.
Non-serious AEs of special interest for this study include the following:

Suspected seizure activity

Confirmed QTcF value of CTCAE Grade 2 or 480-500 msec (see Appendix 4)

Confirmed QTcF value exceeding a change from baseline of 60 msec

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.6.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
79/Protocol BP39207, Version 5

Confirmed increase of serum creatinine exceeding 1.5ULN.

Worsening of psychosis.

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product. This term applies only when a 
contamination of the study drug is suspected.
5.1.4
Selected Safety Assessments 
Additional safety data will be obtained on the following:

The ECG parameters HR, PQ (PR), QRS, QT, RR and QTcF, along with 
information on T- and U-waves.

Changes in ECG parameters as compared to baseline ECG.

Incidence of clinically significant ECG abnormalities. 

Incidence of laboratory abnormalities, based on hematology, clinical chemistry, 
and urinalysis test results:
o
Hematology: Hemoglobin, hematocrit, RBCs, platelets, WBCs, differentials (counts): 
neutrophils, eosinophils, lymphocytes, monocytes, basophils.
o
Blood chemistry: AST, ALT, total and conjugated bilirubin, ALP, albumin, creatinine, 
urea, total protein, total cholesterol, LDL and HDL cholesterol, triglycerides, sodium, 
chloride, calcium, phosphate, potassium, glucose (fasting).
o
Urinalysis: protein, blood, glucose, leukocytes, nitrites and pH.

Changes in extrapyramidal symptoms as assessed by the ESRS-A scale.

Changes in the positive symptoms and excitement/hostility as assessed by the 
respective PANSS factors (see Section 4.6.1.8). 

Suicidality assessed by the Columbia Suicide Severity Rating Scale (C-SSRS).

Psychopathological assessment assessed by the NOSIE.
5.2
SAFETY PLAN
The Safety Plan considers observations made in non-clinical investigations including 
GLP toxicology studies in rats and dogs and the observations made in clinical trials. 
Hypothetical considerations are included in the interpretation of non-clinical and clinical 
data.
The safety monitoring and the frequency of the scheduled visits are described in 
Appendix 1. All safety data will be reviewed throughout the study by the Sponsor in a 
treatment-blinded manner. However, the safety IMC will review the unblinded safety data 
obtained during the in-patient stay of the first 40 patients. The following sections specify 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
80/Protocol BP39207, Version 5
some of the monitoring measures that will be taken to maximize the participant’s safety 
in this study. 
5.2.1
Management of Specific Adverse Events 
5.2.1.1
Changes in Heart Rate and Blood Pressure 
Despite the increases in heart rate and BP observed in preclinical and Phase I studies 
(see Sections 
and 1.2.2.1), similar results were not observed in the MAD study in 
Down syndrome subjects (Study BP25543) nor in the safety review of BP27832 
(CLEMATIS). Vital signs and ECG assessment of the heart rate will be performed 
throughout the study. Additional assessments of vital signs might be considered by the 
Investigator. 
5.2.1.2
Changes in QTcF Interval
Increased QTcF intervals at supratherapeutic plasma concentrations have been 
observed in the context of the basmisanil DDI study with itraconazole, a strong CYP3A4 
inhibitor. The average maximum concentration was ~ 4-fold higher than the anticipated 
exposure with 240 mg BID in the current study. Following dosing of basmisanil up to 
360 mg BID in the absence of a CYP3A4 inhibitor, categorical analyses of QTc change 
do not point at a clinically relevant effect  and there was no subject with a QTcF interval 
above 500 msec or with a change from baseline by more than 60 msec. Since patients 
with schizophrenia may be receiving atypical antipsychotics which may prolong QTc, 
QTc interval will be monitored at the initiation of basmisanil treatment to address this risk.
ECG recordings are part of the safety monitoring of this study. Stopping rules are 
provided in line with Roche standard procedures (see Section 3.1.2).
5.2.1.3
Increases in Serum Creatinine 
A mild increase in serum creatinine not exceeding the ULN and without concomitant 
changes in BUN and electrolytes, respectively, was observed in previous clinical trials in 
healthy volunteers and in people with Down syndrome. Since the increases in serum 
creatinine have not been associated with changes of other GFR markers, it is likely 
related to inhibitory effects of basmisanil on the tubular creatinine transporters as shown 
in vitro. In this study, serum creatinine will be measured at various time-points and an 
increase exceeding1.5 ULN that is confirmed by a repeat testing within three days will 
result in withdrawal. 
5.2.1.4
Suicidality 
Clinical experience does not point to any suicidality liability of basmisanil. However, 
monitoring for suicidality (see C-SSRS in Section 4.6.1.8) is mandatory in clinical trials of 
CNS active molecules and will be implemented as outlined in Appendix 1 with the C-
SSRS. The Investigator is asked to assess individually appropriate next steps in case a 
suicidality alert arises. 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
81/Protocol BP39207, Version 5
5.2.1.5
Withdrawal Symptoms 
At the current time, neither non-clinical nor clinical observations point to a liability of 
withdrawal symptoms after stopping basmisanil treatment. Nevertheless, AE monitoring 
(including a phone call by the Investigator 7 days after the last dose) is continued for 
about 4 weeks after the last dose which is considered appropriate in the context of a 
dominant half-life of less than 12 hours. Should withdrawal symptoms occur, 
symptomatic treatment is recommended. Reintroducing basmisanil is not foreseen.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all AEs (see Section 5.1.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.4-5.6. 
For each AE recorded on the Adverse Event eCRF, the Investigator will make an 
assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on AEs at each patient contact. All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record. AEs will then be reported on the Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies). Any other adverse event should not be 
reported.
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported until 4 weeks after the last dose of study drug.
After this period, Investigators should report any deaths, SAEs, or other AEs of 
concern that are believed to be related to prior treatment with study drug (see Section 
5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation time-points. Examples of non-directive questions 
include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
82/Protocol BP39207, Version 5
5.3.3
Assessment of Severity of Adverse Events
Table 2 provides guidance for assessing AE severity.
Table 2
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see Section 5.1.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an AE is considered to be related to the study drug, indicating "yes" or "no" 
accordingly. The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug.

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable).

Known association of the event with the study drug or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factors in the patient or use of concomitant medications known 
to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event.
For patient receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF. Avoid colloquialisms and abbreviations.
Only one AE term should be recorded in the event field on the Adverse Event eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
83/Protocol BP39207, Version 5
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
5.3.5.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. However, medically significant AEs occurring secondary to an 
initiating event that are separated in time should be recorded as independent events on 
the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time-points. Such events should only be recorded once on the Adverse Event 
eCRF. The initial severity of the event should be recorded, and the severity should be 
updated to reflect the most extreme severity any time the event worsens. If the event 
becomes serious, the Adverse Event eCRF should be updated to reflect this.
A recurrent AE is one that resolves between patient evaluation time-points and 
subsequently recurs. Each recurrence of an AE should be recorded separately on the 
Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be 
reported as an AE if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
84/Protocol BP39207, Version 5

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 times the ULN associated with cholecystitis), only the diagnosis 
(i.e., cholecystitis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE. For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported 
as an AE if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high BP), only the diagnosis (i.e., hypertension) should be recorded on the 
Adverse Event eCRF.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
85/Protocol BP39207, Version 5
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (≥2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (see 
Section 3.1.2). Therefore, Investigators must report as an AE the occurrence of either of 
the following:

Treatment-emergent ALT or AST3ULN in combination with total bilirubin
≥ 2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.
5.3.5.7
Deaths
All deaths that occur during the protocol-specified AE reporting period (see Section 
5.3.1), regardless of relationship to study drug, must be recorded on the Adverse Event 
eCRF and immediately reported to the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
The term “sudden death” should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within one hour of the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable. 
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”).


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
86/Protocol BP39207, Version 5
5.3.5.9
Worsening of Symptoms Associated with Schizophrenia
Worsening of symptoms associated with schizophrenia should be recorded as an AE if 
judged by the Investigator to have unexpectedly worsened in severity or frequency or 
changed in nature at any time during the study. When recording an unanticipated 
worsening of symptoms associated with schizophrenia on the Adverse Event eCRF, it is 
important to convey the concept that the condition has changed by including applicable 
specific descriptors (e.g., exacerbation of psychotic symptoms of schizophrenia 
characterized by “increase of auditory hallucinations”).
A worsening of symptoms of schizophrenia does not necessarily constitute a reason for 
withdrawal of the subject from the study. Appropriate changes in antipsychotic or other 
pharmacological (i.e., antidepressants) treatment can be instituted if discussed with and 
agreed to by the Medical Monitor/Sponsor, and should be recorded in the treatment 
section of the AE eCRF form.
5.3.5.10
New occurrence or worsening of Extrapyramidal Symptoms 
(EPS) 
Worsening of extrapyramidal symptoms associated with antipsychotic treatment and/or 
wash-out of prohibited medication should be recorded as an AE if judged by the 
Investigator to have worsened in severity or frequency or changed in nature at any time 
during the study. 
New occurrence or worsening of EPS does not necessarily constitute a reason for 
withdrawal of the subject from the study. Appropriate decrease in antipsychotic 
medication dosage or other pharmacological (i.e., propanolol) treatment can be instituted 
if discussed with and agreed to by the Medical Monitor/Sponsor, and should be recorded 
in the treatment section of the AE eCRF form.
5.3.5.11
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as a SAE (per the definition of SAEs in Section 5.1.2), except as outlined 
below.
The following hospitalization scenarios are not considered to be SAEs:

Planned hospitalization required by the protocol.

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
o
The patient has not suffered an AE.
o
Prolonged hospitalization due to psychosocial issues such as lack of 
home care facilities, caregiver issues, transport issues, etc.


 
RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd 
87/Protocol BP39207, Version 5 
The following hospitalization scenarios are not considered to be SAEs, but should be 
reported as AEs instead: 
 
Hospitalization for an AE that would ordinarily have been treated in an out-patient 
setting had an out-patient clinic been available. 
 
A hospitalization of the patient does not necessarily constitute a reason for withdrawal of 
the patient from the study (for instance, a short hospitalization for psychosocial reasons 
may be acceptable). Each case should be discussed with the Medical Monitor/Sponsor. 
It should be determined if the patient can continue the study medication while 
hospitalized. In case study medication cannot be continued while the patient is 
hospitalized, it should be determined whether the hospitalization is of such duration that 
a continuation in the study after discharge can be justified. The decision should be 
recorded in the eCRF. 
5.3.5.12 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study drug is not 
an AE unless it results in untoward medical effects.  
Any study drug overdose or incorrect administration of study drug should be noted on 
the Additional Observations eCRF. 
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. If the associated AE fulfills serious criteria, the 
event should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
Appropriate supportive treatment should be initiated according to the individual's clinical 
signs and symptoms and in accordance with best medical practices. In vitro studies have 
shown that benzodiazepines compete with basmisanil for binding to GABAA receptors, 
and flumazenil was also able to block the inhibitory effect of basmisanil on GABA-
induced currents. Benzodiazepines may therefore be considered as a treatment option 
for the management of basmisanil overdose. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR  
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
SAEs. 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
88/Protocol BP39207, Version 5

Non-serious AEs of special interest (see Section 5.1.3).

Pregnancies.
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis.

Significant new diagnostic test results.

Change in causality based on new information.

Change in the event’s outcome, including recovery.

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting SAEs to the local 
Health Authority and IRB/EC.
5.4.1
Emergency Medical Contacts
To ensure the safety of study patients, access to the Medical monitors is available 
24 hours a day 7 days a week. Medical monitors contact details are listed in the 
“Protocol Administrative and Contact Information & List of Investigators”.  
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
For reports of SAEs and non-serious AEs of special interest (see Sections 5.1.2 and 
5.1.3), Investigators should record all case details that can be gathered on the Serious 
Adverse Event Reporting Form and forward this form to the SAE Responsible within 24 
hours.
5.4.3
Reporting Requirements for Pregnancies 
5.4.3.1
Pregnancies in Female Participants 
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 4 weeks after the last 
dose of study drug. A Clinical Trial Pregnancy Reporting Form should be completed by 
the Investigator and submitted to the Sponsor within 24 hours after learning of the 
pregnancy. Pregnancy should not be recorded on the Adverse Event eCRF. The 
Investigator should discontinue study drug and counsel the participant/caregiver, 
discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring of 
the participant should continue until conclusion of the pregnancy. 
5.4.3.2
Pregnancies in Female Partners of Male Study Subjects
Male patients will be instructed through the ICF to immediately inform the Investigator if 
their partner becomes pregnant during the study or within 4 weeks after the last dose of 
study drug. A Clinical Trial Pregnancy Reporting Form should be completed by the 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
89/Protocol BP39207, Version 5
Investigator and submitted to the Sponsor within 24 hours after learning of the 
pregnancy. Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male study subject exposed to study drug. 
The pregnant partner will need to sign an Authorization For Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy. Once the 
authorization has been signed, the Investigator will update the Clinical Trial Pregnancy 
Reporting Form with additional information on the course and outcome of the pregnancy. 
An Investigator who is contacted by a male study subject or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions 
Any spontaneous abortion should be classified as a SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.4.3.4
Congenital Anomalies/Birth defects 
Any congenital anomaly/birth defect in a child born to a female patient should be 
classified as a SAE, recorded on the AE eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the patient is lost to follow-up, 
or the patient withdraws consent. Every effort should be made to follow all serious AEs 
considered to be related to study drug or trial-related procedures until a final outcome 
can be reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 5.4.3.
5.5.2
Sponsor Follow-Up
For SAEs, non-serious AEs of special interest, and pregnancies, the Sponsor or a 
designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
90/Protocol BP39207, Version 5
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Investigator is not required to actively monitor patients for AEs after the end of the 
AE reporting period (defined as 4 weeks after the last dose of study drug). 
If the Investigator becomes aware of any other SAE occurring after the end of the AE 
reporting period, if the event is believed to be related to prior study drug treatment the 
event should be reported directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the Serious Adverse Event Reporting Form using the fax number 
or email address provided to Investigators. 
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and non-serious AEs of special interest 
against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to Investigators, IRBs, ECs, and applicable Health 
Authorities based on applicable legislation.
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the Basmisanil Investigator’s Brochure.
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
Based on current withdrawal rates, approximately 231 patients will be enrolled in the 
study, to ensure that a minimum of 150 patients (50 patients per treatment arm) will have 
evaluable data at 24 weeks. They will be randomized 1:1:1 to the three study arms.
A sample size of 50 patients per arm provides 80% power to detect a treatment effect 
size of 0.5, at a 2-sided -level of 0.1, for the pairwise comparison of each active dose 
arm to placebo. No adjustments for multiple comparisons will be incorporated into the 
analysis. Incorporating an assumed withdrawal rate of 35%, a study sample size of 231 
(77 patients per arm) will be used. The sample size may be increased if the actual 
withdrawal rate is higher than expected.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
91/Protocol BP39207, Version 5
6.2
SUMMARIES OF CONDUCT OF STUDY
To determine whether the integrity of the study was maintained, listing/summary of data 
referring to the general conduct of the study (such as enrollment, protocol violations, use 
of prohibited co-medication, blinding details) will be generated.
6.3
ANALYSIS POPULATIONS
6.3.1
Safety Analysis Population
All patients who have received at least one administration of the study treatment, 
whether prematurely withdrawn from the study or not, will be included in the safety 
analysis. For the safety analysis population, data will be analyzed according to the 
treatment actually taken.
6.3.2
Efficacy Analysis Population
The following analysis populations will be defined: intent-to-treat (ITT) and per-protocol 
(PP). For both populations, patients will be grouped according to the treatment actually 
taken.
Intent-to-treat Population
The ITT population is defined as consisting of all patients randomized, who received at 
least one administration of the study treatment and had a baseline and at least one 
post-dose assessment. 
Per-Protocol Population
The PP population will be precisely defined in a separate document, before database 
closure, as the subset of the ITT population without major protocol deviations.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographics, baseline characteristics and all baseline laboratory values will be 
summarized descriptively by treatment using frequency tables and summary statistics as 
appropriate.
6.5
SAFETY ANALYSES
All safety analysis will be based on the safety analysis population.
As appropriate, listings, summary tables and graphs will be provided for safety and 
tolerability assessments, including:

Incidence of AEs (overall, by intensity and by relationship to study medication).

Incidence of SAEs.

Incidence of laboratory abnormalities (including hematology, clinical chemistry, and 
urinalysis parameters).

Incidence of BP abnormalities.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
92/Protocol BP39207, Version 5

Incidence of ECG abnormalities as well ECG changes as compared to baseline 
measurements.

Changes in the PANSS as compared to baseline.

NOSIE-30 as compared to baseline.

Changes in C-SSRS as compared to baseline.
Further details on the safety parameters are given in Section 5.1. Safety data will be 
summarized using descriptive statistics using the safety analysis population, which will 
include all patients treated.
6.5.1
Adverse Events
The original terms recorded on the eCRF by the Investigator for AEs will be standardized 
by the Sponsor.
AEs will be summarized by mapped term and appropriate thesaurus level.
6.5.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Patient listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 
d’Unités). Laboratory data not reported in SI units will be converted to SI units before 
processing.
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges.
6.5.2.1
Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters. For most parameters, the measured laboratory test result 
will be assessed directly using the Roche standard reference range. Certain laboratory 
parameters will be transformed to Roche’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and ALP and total bilirubin. Since the standard reference ranges 
for these parameters have a lower limit of zero, only the upper limits of the ranges will be 
used in transforming the data.
6.5.2.2
Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche pre-defined standard 
reference range. Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in patient listings of laboratory data.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
93/Protocol BP39207, Version 5
In addition to the standard reference range, a marked reference range has been 
pre-defined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a patient, the midpoint of the standard reference range will be used as the 
patient’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the patient listings as 
“HH” for very high or “LL” for very low.
6.5.3
Vital Signs
Vital signs data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate.
6.5.4
ECG Data Analysis
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate.
6.5.5
Concomitant Medications
The original terms recorded on the patients’ eCRF by the Investigator for concomitant 
medications will be standardized by the Sponsor by assigning preferred terms.
Concomitant medications will be presented in summary tables and listings.
6.6
EFFICACY ANALYSES
The primary analysis population for all efficacy analyses will be based on the ITT 
population, which will include all randomized patients treated with study medication. 
6.6.1
Primary Efficacy Endpoint
The primary efficacy endpoint is:

Cognition assessed by the mean change from baseline in the MCCB neurocognitive 
composite score
The primary efficacy endpoint (change from baseline to Week 24 in MCCB 
neurocognitive composite score) will be analyzed using a mixed effect model for 
repeated measures (MMRM) with treatment, region, age group, sex, schizophrenia 
cognitive subtype, and visit as fixed effects, treatment-by-visit interaction term, and 
baseline value as the covariate. The model will include subject as a random effect, and 
incorporate an unstructured variance-covariance matrix. For each active dose arm 
tested at the final analysis, this model will be used to test the null hypothesis of no 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
94/Protocol BP39207, Version 5
treatment difference between the placebo arm and the active arm at a 2-sided -level of 
0.1.
6.6.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

Mean change from baseline in MCCB cognitive domain scores (attention, speed of 
processing, reasoning, working memory, visual learning, verbal learning and social 
cognition).

Mean change from baseline in the WMS IV-PAL score.

Mean change from baseline in the WMS IV-LM score.

Mean change from baseline in the ratio between TMT-B and TMT-A scores.

Mean change from baseline in the SCoRS score.

Mean change from baseline in the CGI-S rating.

Mean change from baseline in the CGI-I rating.

Mean change from baseline in the PSP total score.
Continuous secondary efficacy endpoints will be analyzed using an MMRM model 
similar to that described for the primary endpoint, and summarized using descriptive 
statistics.
6.7
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Individual and mean plasma concentrations at each sampling time-point will be 
presented by listings and descriptive summary statistics, including means, medians, 
geometric means, ranges, standard deviations, and coefficients of variation. Individual 
and mean plasma concentration versus time data will be plotted on semi-logarithmic 
scales.
Graphical exploration of the relationship between basmisanil (and M1 and other 
metabolites, if relevant) exposure and outcome measures as well as safety parameters 
will be performed. If indicated by such exploration, more formal analyses of PK to PD 
parameters of interest may be undertaken.
6.8
PATIENT-REPORTED OUTCOME ANALYSES
The patient-reported outcomes are:

Change from baseline on the patient-reported health-related quality of life scale 
(SQLS).


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
95/Protocol BP39207, Version 5

Change in subjective mood, sleep and subjective well-being and cognitive 
functioning ratings.
These endpoints will be analyzed using an MMRM model similar to that described for the 
primary endpoint, and summarized using descriptive statistics.
6.9
EXPLORATORY ANALYSES
The exploratory analyses will include:

Mean change from baseline in the PANSS factor and total scores.

Mean change from baseline in the BNSS subscales and total scores.

Mean change from baseline in % of patients rated as “ready to work” on the WoRQ.

Mean change from baseline in the VRFCAT score.

Mean change from baseline in the CFAS score.

Semantic priming analysis of verbal fluency, as described in Section 4.6.1.8.

Primacy region analysis of episodic verbal learning and recall. Percentage recall 
from the primacy relative to the recency region will be calculated for each learning 
trial and for long-delay free recall. 

Analysis of genetic PRS and complement C4 CNV as described in Section 3.2.3, 
and the 15q11-q13 chromosomal region including the GABRs GABRB3, GABRB5 
and GABRG3 genes. 
These endpoints will be analyzed using an MMRM or ANCOVA model as appropriate, 
and summarized using descriptive statistics. 
6.10
INTERIM ANALYSES
An interim analysis will be conducted when approximately 30 patients per arm have 
completed the first 12 weeks of treatment. The analysis will be conducted by the efficacy 
IMC as described in Section 3.1.3.2.
This analysis will focus on the change from baseline to Week 12 in MCCB 
neurocognitive composite score, which will be analyzed using an MMRM model which 
will be similar to that described for the primary analysis (including all stratification factors 
although this may not be possible depending on the actual cell size). The pairwise 
comparison of each active dose to placebo will be evaluated using the estimated effect 
size based on the least-squares mean (LSM) estimates from the MMRM models. For 
each dose arm, the decision whether to continue or drop the arm for the remainder of 
the study will be based on the conditional probability that the true treatment effect size 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
96/Protocol BP39207, Version 5
for that arm is0.35. If the calculated conditional probability is less than 20% that the 
true treatment effect size can reach this threshold for one of the two doses, then that 
dose arm may be discontinued. If this conditional probability is less than 20% for both 
dose arms, then the study may be discontinued for futility. 
In case the calculated conditional probability that the true treatment effect size can 
reach the threshold of effect size > 0.35 is more than 20% for both treatment arms, one 
treatment arm may still be discontinued. 
Further analysis details on the interim analysis will be documented in a separate 
Efficacy IMC Agreement Document prior to the conduct of the interim analysis.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Sites will be responsible for data entry into the Electronic Data 
Capture (EDC) system.
A comprehensive validation check program will verify the data. Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the Investigator.
The Sponsor will produce a Data Handling Manual and a Data Management Plan that 
describes the quality checking to be performed on the data. Data collected electronically 
will be sent directly to the Sponsor, using the Sponsor’s standard procedures to handle 
and process the electronic transfer of these data.
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
Contract research organizations (CROs) may also be responsible for quality checking of 
the data or parts of the data. In this case and in the event of discrepant data, the CRO 
will request data clarification from the sites, which the sites will resolve electronically in 
the EDC system as appropriate.
If responsible for quality checking of data, the CRO will produce a Data Management 
Plan or equivalent document that describes the quality checking to be performed on the 
data. System backups for data stored at the CRO and records retention for the study 
data will be consistent with the CRO’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an on line EDC system. The data collected in the 
source documents is entered onto the study eCRF. An audit trail will maintain a record of 
initial entries and changes made; reasons for change; time and date of entry; and user 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
97/Protocol BP39207, Version 5
name of person authorizing entry or change. For each patient enrolled, an eCRF must 
be completed and electronically signed by the PI or authorized delegate from the study 
staff. If a patient withdraws from the study, the reason must be noted on the eCRF. If a 
patient is withdrawn from the study because of a treatment‑limiting AE, thorough efforts 
should be made to clearly document the outcome.
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor/CRO in the eCRFs and in all required reports.
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO.
At the end of the study, the Investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X‑rays, 
patient files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical trial.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
98/Protocol BP39207, Version 5
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the PI for at least 
15 years after completion or discontinuation of the study, or for the length of time 
required by relevant national or local Health Authorities, whichever is longer. After that 
period of time, the documents may be destroyed, subject to local regulations. No records 
may be disposed of without the written approval of the Sponsor. Written notification 
should be provided to the Sponsor prior to transferring any records to another party or 
moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws. Studies 
conducted in the EU/EEA will comply with the EU Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site. If applicable, it will be provided in a certified translation of the 
local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission. The final IRB/EC‑approved Consent Forms must be provided to the 
Sponsor for Health Authority submission purposes according to local requirements.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
99/Protocol BP39207, Version 5
In this study, the informant will be asked to provide information useful to assess patient 
eligibility and to complete clinician rated scales. A separate written informed consent will 
be obtained from the informant.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
In this study, the Investigator or Designee shall assess the capacity of the patient to give 
informed consent while discussing the study and the Consent Forms. This assessment 
shall be confirmed by the results of the ESC form (see Inclusion Criteria Section 4.2.2 ) 
and the IQ measure (see Exclusion Criteria, Section 4.2.3) done during the Screening 
Visit.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for Health Authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. HIPAA of 1996. If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, and 
other processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the PI and 
reviewed and approved by the IRB/EC before the study is initiated. In addition, any 
patient recruitment materials must be approved by the IRB/EC.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
100/Protocol BP39207, Version 5
The PI is responsible for providing written summaries of the status of the study to the 
IRB/EC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. Investigators are also responsible for promptly 
informing the IRB/EC of any protocol amendments (see Section 9.5).
In addition to the requirements for reporting all AEs to the Sponsor, Investigators must 
comply with requirements for reporting SAEs to the local Health Authority and IRB/EC. 
Investigators may receive written IND safety reports or other safety‑related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with Health Authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local Health Authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLO).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
101/Protocol BP39207, Version 5
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the Investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data.
Roche shall also submit a Development Safety Update Report (DSUR) once a year to 
the Independent Ethics Committee (IEC) and Health Authorities according to local 
regulatory requirements and timelines of each country participating in the study.
It is the understanding of the Sponsor that this protocol (and any modifications) as well 
as appropriate consent procedures and advertisements, will be reviewed and approved 
by an IRB. This board must operate in accordance with the current Federal Regulations. 
The Sponsor will be sent a letter or certificate of approval prior to initiation of the study, 
and also whenever subsequent amendments /modifications are made to the protocol. 
Roche shall also submit an IND Annual Report to the FDA according to local regulatory 
requirements and timelines.
9.2
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs. The Investigator will 
permit national and local Health Authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.3
ADMINISTRATIVE STRUCTURE
This study will be conducted using the services of a CRO managed by Roche. The CRO 
will manage the vendors required to provide services such as cardiac monitoring, IXRS, 
event planning, central laboratories, scale management and cognitive testing and Roche 
will maintain oversight. The study will utilise an IMC consisting of Roche personnel.
9.4
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
The results of this study may be published or presented at scientific meetings by the 
Sponsor or designated Investigators. If this is foreseen, the Investigator agrees to submit 
all manuscripts or abstracts to the Sponsor prior to submission. All publications have to 
be approved by the Sponsor. This allows the Sponsor to protect proprietary information 
and to provide comments based on information from other studies that may not yet be 
available to the Investigator.
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator may be designated by mutual agreement.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
102/Protocol BP39207, Version 5
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel.
Authorship will be determined by mutual agreement and in-line with International 
Committee of Medical Journal Editors authorship requirements.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.5
PROTOCOL AMENDMENTS
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or any non-substantial changes, as defined by 
regulatory requirements.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
103/Protocol BP39207, Version 5
10.
REFERENCES
Atkinson RC and Shiffrin RM. Human memory: A proposed system and its control 
processes. In Spence KW and J. L. Spence JL, editors. The psychology of learning 
and motivation: Advances in research and theories. New York: Academic Press, 
1968:89-195.
Ballard TM, Knoflach F, Prinssen E, et al. RO4938581, a novel cognitive enhancer 
acting at GABAA a5 subunit-containing receptors. Psychopharmacol. 
2009;202:207-223.
Benes FM. Building models for postmortem abnormalities in hippocampus of 
schizophrenics. Schizophr Res. 2015;167(1-3):73-83.
Beneyto M, Abbott A, Hashimoto T, et al. Lamina specific alterations in cortical GABA(A) 
receptor subunit expression in schizophrenia. Cereb Cortex. 2011;21(5):999–1011.
Bergen SE, Fanous AH, Walsh D, et al. Polymorphisms in SLC6A4, PAH, GABRB3, and 
MAOB and modification of psychotic disorder features. Schizophr Res. 
2009;109(1–3):94–97.
Brébion G, Bressan RA, Ohlsen RI, et al. Production of atypical category exemplars in 
patients with schizophrenia. Journal of the International Neuropsychol Soc. 
2010;16(5):822–828.
Brébion G, Stephan-Otto C, Huerta-Ramos E, et al. Abnormal functioning of the 
semantic network in schizophrenia patients with thought disorganization. An 
exemplar production task. Psychiatry Res. 2013;205(1-2):1–6. 
Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptoms Rating Scale 
(ESRS). Schizophrenia Research. 2005;76 (2-3):247-265. 
Clarkson AN, Huang BS, MacIsaac S, et al. Reducing excessive GABA-mediated tonic 
inhibition promotes functional recovery after stroke. Nature. 2010;468:305-309.
Clarkson AN, Overmann JJ, Zhong S, et al. AMPA receptor-induced local brain-derived 
neurotrophic factor signaling mediates motor recovery after stroke. J Neurosci. 
2011;31:3766-3775.
Collinson N, Kuenzi FM, Jarolimek W, et al. Enhanced learning and memory and altered 
GABAergic synaptic transmission in mice lacking the a5 subunit of the GABAA
receptor. J Neurosci. 2002;22:5572-5580.
Coyle JT. NMDA receptor and schizophrenia: a brief history. Schizophr Bull. 
2012;38(5):920-926.
Crestani F, Keist R, Fritschy JM, et al. Trace fear conditioning involves hippocampal a5 
GABAA receptors. Proc Natl Acad Sci USA. 2002;99:8980-8985.
Davies G, Armstrong N, Bis JC, et al. Genetic contributions to variation in general 
cognitive function: a meta-analysis of genome-wide association studies in the 
CHARGE consortium (N=53949). Mol Psychiat. 2015;20(2):183–192. 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
104/Protocol BP39207, Version 5
Davies G, Marioni RE, Liewald DC, et al. Genome-wide association study of cognitive 
functions and educational attainment in UK Biobank (N=112 151). Mol Psychiatr. 
2016;21(6):758–767. 
Dawson GR, Maubach KA, Collinson N, et al. An inverse agonist selective for a5 
subunit-containing GABAA receptors enhances cognition. J Pharmacol Exp Ther. 
2006;316:1335-1345.
Debette S, Ibrahim Verbaas CA, Bressler J, et al. Genome-wide studies of verbal 
declarative memory in nondemented older people: the Cohorts for Heart and Aging 
Research in Genomic Epidemiology consortium. Biol Psychiatry 2015;77(8):749–
763. 
Foldi N, Kivisaari S, Monsch A, et al. Neural correlates of the serial position effects in 
dementia: A voxel-based morphometry study. Alzheimer’s & Dementia. 
2011;7(4):S26.
Green MF. Neurocognitive deficits and functional outcome in schizophrenia: are we 
measuring the "right stuff"? J Schizophr Bull. 2000;26(1):119-136.
Guy W., ed. Clinical Global Impressions: In ECDEU Assessment Manual for 
Psychopharmacology. 1976; 218-222. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health
Hardingham GE, Do KQ. Linking early-life NMDAR hypofunction and oxidative stress in 
schizophrenia pathogenesis. Nat Rev Neurosci. 2016;17(2):125-134.
Hirni DI, Kivisaari SL, Monsch AU, et al. Distinct neuroanatomical bases of episodic and 
semantic memory performance in Alzheimer’s disease. Neuropsychol.
2013;51:930–937. 
Honigfeld G, Gillis RD, Klett CJ. NOSIE-30: a tretment-sensitive ward behavior scale. 
Psychol Rep. 1966;19(1):180-182.
Huang CC, Cheng MC, Tsai HM, et al. Genetic analysis of GABRB3 at 15q12 as a 
candidate gene of schizophrenia. Psychiatr Genet. 2014;24(4):151–157.
Inada T, Koga M, Ishiguro H, et al. Pathway-based association analysis of genome-wide 
screening data suggest that genes associated with the gamma-aminobutyric acid 
receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant 
tardive dyskinesia. Pharmacogenet Genomics. 2008;18(4):317–323.
Investigator’s Brochure, Basmisanil (RO5186582)-GABAA 5 negative allosteric 
modulator, Version 10, June 2018.
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-76.
Keefe RS, Silva SG, Perkins DO, et al. The effects of atypical antipsychotic drugs on 
neurocognitive impairment in schizophrenia: A review and meta-analysis. 
Schizophr Bull. 1999;25:201–222.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
105/Protocol BP39207, Version 5
Keefe RS, Davis VG, Spagnola NB, et al. Reliability, validity, and treatment sensitivity of 
the Schizophrenia Cognition Rating Scale. Eur Neuropsychopharmacol. 
2015;25(2):176-184.
Keefe RS, Davis VG, Atkins AS, et al. Validation of a computerized test of functional 
capacity. Schizophr Res. 2016;pii:S0920-9964(16)30130-X (epub ahead of print).
Lewis DA, Cruz D, Eggan S, et al. Postnatal development of prefrontal inhibitory circuits 
and the pathophysiology of cognitive dysfunction in schizophrenia. Ann N Y Acad 
Sci. 2004;1021:64-76.
Lodge DJ, Grace AA. Hippocampal dysregulation of dopamine system function and the 
pathophysiology of schizophrenia. Trends Pharmacol Sci. 2011;32(9):507-513.
Malhotra D, Sebat J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. 
Cell. 2012;148(6):1223-1241.
Marder SR and Chouinard G. The effects of risperidone on the five dimensions of 
schizophrenia derived by factor analysis: combined results of the North American 
trials. J. Clin. Psychiatry. 1997; 58(12):538–546.
Martin CR and Allan R. Factor structure of the Schizophrenia Quality of Life Scale 
Revision 4 (SQLS-R4). Psychol Health Med. 2007;12(2):126-34.
Martínez-Cué C, Martínez P, Rueda N, et al. Reducing GABAA α5 receptor-mediated 
inhibition rescues functional and neuromorphological deficits in a mouse model of 
Down syndrome. J Neurosci. 2013;33(9):3953-3966.
McRae K, Cree GS, Seidenberg MS, et al. Semantic feature production norms for a 
large set of living and nonliving things. Behav Res Methods, Instruments, and 
Computers. 2005;37:547–559.
McRae K, de Sa VR, Seidenberg MS. On the nature and scope of featural 
representations of word meaning. J Exp Psychol Gen. 1997;126:99–130.
Minzenberg MJ, Carter CS. Developing treatments for impaired cognition in 
schizophrenia. Trends Cogn Sci. 2012;1:35-42.
Morosini PL, Magliano L, Brambilla L, et al. Development, reliability and acceptability of 
a new version of the DSM-IV Social and Occupational Functioning Assessment 
Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 
2000;101(4):323-9.
Möhler H, Rudolph U. Selective GABAA circuits for novel CNS drugs. Drug Discov. 
Today. 2004;1:117-123.
Nuechterlein KH, Green MF, Kern RS, et al. The MATRICS Consensus Cognitive 
Battery: part 1. Test selection, reliability, and validity. Am J Psychiatry. 
2008;165:203–213. 


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
106/Protocol BP39207, Version 5
Nutt DJ, Besson M, Wilson SJ, et al. Blockade of alcohol's amnestic activity in humans 
by an a5 subtype benzodiazepine receptor inverse agonist. Neuropharmacol. 
2007;53:810-820.
Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor 
properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013;14:383–400.
Posner K, Brown GK, Stanley B, et al., The Columbia-Suicide Severity Rating Scale: 
Initial Validity and Internal Consistency Findings From Three Multisite Studies With 
Adolescents and Adults American Journal of Psychiatry, 2011; 168:1266-1277.
Potkin SG, Bugarski-Kirola D, Edgar CJ, et al. Psychometric evaluation of the Work 
Readiness Questionnaire in schizophrenia. CNS Spectr. 2016 Apr;21(2):199-206.
Povroznik JM, Rudy CC, Hunsberger HC, et al. Effects of an α5 GABAA inverse agonist 
on MK-801-induced learning deficits in an incremental repeated acquisition task. 
Behav Pharmacol. 2014;25:331–335.
Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of 
schizophrenia and bipolar disorder. Nature. 2009;460(7256):748–752. 
RDR1066029: Study of the effect of chronic administration of GABAA 5 negative 
allosteric modulators (NAMs) on functional recovery after stroke. In preparation.
Rees E, Walters JT, Georgieva L, et al. Analysis of copy number variations at 15 
schizophrenia-associated loci. Br J Psychiatr. 2014;204(2):108-114.
Redrobe JP, et al. Negative modulation of GABAA α5 receptors by RO4938581 
attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced 
cognitive deficits in rats. Psychopharmacol. 2012;221:451–468.
Reichenberg A, Caspi A, Harrington H, et al. Static and dynamic cognitive deficits in 
childhood preceding adult schizophrenia: A 30-year study. Am J Psychiatry. 
2010;167:160–169.
Ripke S, Neale BM, Corvin A,et al. Biological insights from 108 schizophrenia-
associated genetic loci. Nature. 2014;511(7510):421–427. 
Rosch E, Mervis CB, Gray WD, et al. Basic objects in natural categories. Cognitive 
Psychol. 1976;8:382–439.
Ruse SA, Harvey PD, Davis VG, et al. Virtual reality functional capacity assessment in 
schizophrenia: Preliminary data regarding feasibility and correlations with cognitive 
and functional capacity performance. Schizophren Res Cogn. 2014;1(1):e21-e26.
Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of 
complement component 4. Nature. 2016;530(7589):177–183. 
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric 
Interview (M.I.N.I.): the development and validation of a structured diagnostic 
psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 
Suppl 20:22-33 quiz 34-57.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
107/Protocol BP39207, Version 5
Sigurdsson T and Duvarci S. Hippocampal-Prefrontal Interactions in Cognition, Behavior 
and Psychiatric Disease. Front Syst Neurosci. 2016;9:190.
Strauss G, Keller W, Buchanan R, et al. Next-generation negative symptom assessment 
for clinical trials: Validation of the Brief Negative Symptom Scale. Schizophrenia 
Research 2012;142:88–92.
Sun J, Jayathilake K, Zhao Z, et al. Investigating association of four gene regions 
(GABRB3, MAOB, PAH, and SLC6A4) with five symptoms in schizophrenia. 
Psychiatry Res. 2012;198(2):202–206.
Taylor KI, Devereux BJ, Acres K, et al. Contrasting effects of feature-based statistics on 
the categorization and basic-level identification of visual objects. Cognition. 
2011;122(3):363-374.
Timić Stamenić T, Joksimović S, Biawat P, et al. Negative modulation of 5 GABAA
receptors in rats may partially prevent memory impairment induced by MK-801, but 
not amphetamine- or MK-801-elicited hyperlocomotion. J Psychopharmacol. 
2015;29(9):1013-1024.
Wechsler D. Wechsler Abbreviated Scale of Intelligence-Second Edition (WASI-II). San 
Antonio, TX: NCS Pearson, 2011.
Wechsler D. Administration and scoring manual for the Wechsler Memory Scale 4th 
edition. Pearson, San Antonio, TX, 2009.
Wilkinson G, Hesdon B, Wild D, et al. Self-report quality of life measure for people with 
schizophrenia:The SQLS. British Journal of Psychiatry.2000;177:42–46.
Wilkinson GS, Robertson GJ. Wide Range Achievement Test-4 professional manual. 
Lutz, FL: Psychological Assessment Resources, 2006.


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
108/Protocol BP39207, Version 5
Appendix 1 Schedule of Assessments
Week
Screeninga
Baseline 1b
Baseline 2a,b
Week 2 Week 4 Week 6 Week 9 Week 12a
Week 16 Week 20 Week 24a
F-U1 week 
26 phone 
calll
F-U2 week 
28 
Day
(Up to 5 
weeks)
(up to Day  -14)
Day 1
In-
patients 
only
Days 2, 3, 
4, 5, 6 
Day 7
Day 14
Day 28
Day 42
Day 63
Day 84
Day 112
Day 140
Day 168
Day 182
Day 196
Time Relative (h)
***
***
***
0 ***
144
312
648
984
1488
1992
2664
3336
4008
4344
4680
Visit Window
+/-1
+/-2
+/-2
+/-2
+/-2
+/-2
+/-3
+/-3
+/-3
+/-3
+/-3
Assessments
Informed Consent
x
Evaluation to Sign Consent (ESC)
x
Eligibility
x
Demography
x
Medical History
x
Physical Examination
x
x
n
x
Urine drug screen
x
x
x
x
x
x
Alcohol testing
x
x
x
x
x
x
Pregnancy testc
x
x
x
Vital Signs
x
x
e
x
x
e,h
x
x
x
x
x
x
x
x
x
ECG-12 lead (triplicates)d
x
x
e
x
e,h
x
x
x
x
x
x
x
x
x
Antipsychotic testing
x
Blood Chemistry
x
x
x
x
x
x
x
x
x
x
Hematology
x
x
x
x
x
x
x
x
Coagulation
x
x
x
Serology
x
x
Urinalysis
x
x
x
x
x
Genotyping
x
k
RBR DNA
x
k
Administration of Study Medication
x
x
x
x
x
x
x
x
x
x
x
f
PK Sampled
x
h
x
x
x
x
Benzodiazepine sample
x
x
x
x
Benzodiazepine questions
x
x
x
x
Week 1


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
109/Protocol BP39207, Version 5
Appendix 1 Schedule of Assessments (cont.)
Week
Screeninga
Baseline 1b
Baseline 2a,b
Week 2 Week 4 Week 6 Week 9 Week 12a
Week 16 Week 20 Week 24a
F-U1 week 
26 phone 
calll
F-U2 week 
28 
Day
(Up to 5 
weeks)
(up to Day  -14)
Day 1
In-
patients 
only
Days 2, 3, 
4, 5, 6 
Day 7
Day 14
Day 28
Day 42
Day 63
Day 84
Day 112
Day 140
Day 168
Day 182
Day 196
Time Relative (h)
***
***
***
0 ***
144
312
648
984
1488
1992
2664
3336
4008
4344
4680
Visit Window
+/-1
+/-2
+/-2
+/-2
+/-2
+/-2
+/-3
+/-3
+/-3
+/-3
+/-3
Assessments
MINI
x
WASI-II 4 subtestsg
x
WRAT-4 reading test
x
MCCBm
x
x
x
x
x
x
TMT-part Bm
x
x
x
x
x
x
SCoRS
x
x
x
x
WMS IV -LMm
x
x
x
x
WMS IV-PAL m
x
x
x
x
x
PSP
x
x
x
x
VRFCAT
x
x
x
x
CFAS
x
x
x
x
WoRQ
x
x
x
x
SQLS
x
x
x
x
NOSIE-30h
x
x
x
x
PANSS
x
x
xi,h
xi
x
x
x
x
x
x
x
x
x
ESRS-A
x
x
x
x
x
x
x
CGI-S
x
x
x
x
x
x
x
x
x
x
x
CGI-I
x
x
x
x
x
x
x
x
x
x
BNSS
x
x
x
x
x
x
x
x
x
x
Assessment of suicidality C-SSRS
x
x
x
x
x
x
x
x
x
x
x
x
x
Weekly contact with patient j
x
x
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Previous and Concomitant 
Treatments
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Week 1


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
110/Protocol BP39207, Version 5
Appendix 1 Schedule of Assessments (cont.)
a) can be split over 2 days if preferred
b) baseline visit 1 and baseline visit 2 should be approximately 1 week apart
c) blood test at screening visit
d) to be taken before the morning dose, unless otherwise specified
e) 2 measures to be taken: 1x pre-dose, 1x 4-5 hours after the morning dose (day 1 
and day 7)
f)
The morning dose is the last dose for the study, to be taken from the week 20 
inventory
g) MCCB and WRAT-4 will be video and audio recorded
h) in-patients only
i)
only positive symptoms factor (items P1,P3,P5,P6,N7,G1,G9,G12) and 
hostility/excitement factor (items P4,P7,G8,G14) will be administered
j)
via phone calls when no visit is planned
k) samples can be taken at any time between BL and FU2
l)
the FU1 visit will be conducted by phone to assess the patient’s general condition.
m) cognitive testing should be performed at a similar time of day and in the same 
sequence across all study visits, starting with the MCCB 
n) body weight only


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
111/Protocol BP39207, Version 5
Appendix 2 Antipsychotics Equivalent Dose
The tables below show the approximate marketed equivalent doses of antipsychotics to 
up to a maximum of 6 mg risperidone or 600 mg chlorpromazine, respectively. The 
following principles for the derivation of antipsychotics equivalent doses were applied:
1. The equivalent doses of commonly used antipsychotics follow guidance from
relevant clinical literature and the expert consensus guideline for optimizing 
pharmacologic treatment of psychotic disorders.
2. The table only shows approximate equivalent doses for marketed dose strengths 
and dose ranges in accordance with the label information available (may vary 
from country to country). In practice, doses of antipsychotics should be within
dose ranges approved by the local Health Authority.
3. In practice, if a dose of a given antipsychotic falls in between two doses in the 
table, the higher dose should be used.
4. For antipsychotics that are not listed in the table, the Investigator should contact 
the Medical Monitor before enrolling the patient.








RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
115/Protocol BP39207, Version 5
Appendix 3 Examples of prohibited CYP3A4 inhibitors and 
inducers concomitant medication
Please note that this is not an exhaustive list of prohibited CYP3A4 inhibitors or inducers.
Strong CYP3A4 Inhibitors:

Indinavir

Nelfinavir

Ritonavir

Clarithromycin

Itraconazole

Ketoconazole

Nefazodone

Saquinavir

Subuxone

Telithromycin
Moderate CYP3A4 Inhibitors:

Aprepitant

Erythromycin

Fluconazole

Grapefruit juice

Verapamil

Diltiazem
CYP3A4 Inducers

Efavirenz

Nevirapine

Barbiturates

Carbamazepine

Enzalutamide

Glucocorticoids

Modafinil

Oxcarbazepine

Phenobarbital

Phenytoin

Pioglitazone

Rifabutin

Rifampin

St John’s Wort

Troglitazone
From http://medicine.iupui.edu/CLINPHARM/ddis/main-table


RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd
116/Protocol BP39207, Version 5
Appendix 4 Common Terminology Criteria for Adverse Events 
(CTCAE): QTc Criteria
Investigations
Adverse Event
Grade
1
2
3
4
5
Electrocardiogram
QT corrected 
interval prolonged
QTc 
450-480 ms
QTc 
481-500 ms
QTc 
501 ms on 
at least two 
separate 
ECGs
QTc 501 
or 60 ms change 
from baseline and 
Torsade de pointes 
or polymorphic 
ventricular 
tachycardia or 
signs/symptoms of 
serious arrhythmia
-
Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected 
QT interval.

SAP_001.pdf: 
Official Title: A Phase IIb, Multicenter, Randomized, Double-Blind, Parallel Group, 
Placebocontrolled Study to Evaluate the Efficacy, Safety and 
Tolerability of Basmisanil (RO5186582) as Adjunctive Treatment in 
Patients With Cognitive Impairment Associated With Schizophrenia 
Treated With Antipsychotics 
NCT Number: NCT02953639 
Document Date: SAP Version 1: 29-November-2019