Conditions: Spinal Muscular Atrophy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 35
Healthy volunteers: yes

Brief summary:
This will be a Phase I, 2-part, open-label, non-randomized study to investigate the safety, tolerability, and pharmacokinetics (PK) of a multiple-dosing regimen of risdiplam (Part 1) and the effect of risdiplam on the PK of midazolam (Part 2) following oral administration in healthy adult male and female participants.

Detailed description:

Arms:
arm 1: Participants will receive a dose of 5 milligram (mg) risdiplam once daily (QD) for 14 consecutive days arm 2: All study participants will receive a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with risdiplam will begin. The precise dose will be based on the results of Part 1, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam)

Interventions: intervention 1: Risdiplam intervention 2: Midazolam
Intervention descriptions: intervention 1: Part 1: a dose of 5 milligram (mg) risdiplam QD ; Part 2: precise dose will be based on Part 1 results intervention 2: single dose administration of 2 mg midazolam

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
A Phase I, 2-Part, Open-Label Study to Investigate the Safety, 
Tolerability, and Pharmacokinetics of Multiple Doses of Risdiplam 
and the Effect of Risdiplam on the Pharmacokinetics of Midazolam 
Following Oral Administration in Healthy Participants  
NCT Number: 
NCT03988907  
Document Date: 
Protocol Version 1: 23-April-2019 
 
 
 


FINAL PROTOCOL APPROVAL 
CONFIDENTIAL 
 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (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. 
 
Risdiplam (RO7034067)—F. Hoffmann-La Roche Ltd  
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Protocol BP41361, Version 1 
PROTOCOL 
TITLE: 
A PHASE I, 2-PART, OPEN-LABEL STUDY TO 
INVESTIGATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF MULTIPLE DOSES OF 
RISDIPLAM AND THE EFFECT OF RISDIPLAM ON THE 
PHARMACOKINETICS OF MIDAZOLAM FOLLOWING 
ORAL ADMINISTRATION IN HEALTHY PARTICIPANTS 
PROTOCOL NUMBER: BP41361 
VERSION: 
1 
IND NUMBER: 
128972 
TEST PRODUCT: 
Risdiplam (RO7034067) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic date stamp below 
 
23-Apr-2019 14:02:50
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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Protocol BP41361, Version 1 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE I, 2-PART, OPEN-LABEL STUDY TO 
INVESTIGATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF MULTIPLE DOSES OF 
RISDIPLAM AND THE EFFECT OF RISDIPLAM ON THE 
PHARMACOKINETICS OF MIDAZOLAM FOLLOWING 
ORAL ADMINISTRATION IN HEALTHY PARTICIPANTS 
PROTOCOL NUMBER: BP41361 
VERSION NUMBER: 
1 
IND NUMBER: 
128972 
TEST PRODUCT: 
Risdiplam (RO7034067) 
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 
Site Monitor. 
 


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Protocol BP41361, Version 1 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 2 
1. 
PROTOCOL SUMMARY ............................................................................... 9 
1.1 
Synopsis .................................................................................. 9 
1.2 
Schedule of Activities ............................................................ 13 
2. 
INTRODUCTION ........................................................................................ 18 
2.1 
Overview of the Disease ........................................................ 18 
2.2 
Overview of Risdiplam ........................................................... 18 
2.2.1 
Summary of Clinical Experience ............................................ 19 
2.2.1.1 Safety ................................................................................... 19 
2.2.1.2 Pharmacokinetics ................................................................. 20 
2.3 
Study Rationale ..................................................................... 21 
2.4 
Background ........................................................................... 21 
2.4.1 
Background on Risdiplam ...................................................... 21 
2.4.2 
Background on Midazolam .................................................... 22 
2.5 
Benefit/Risk Assessment ....................................................... 22 
3. 
OBJECTIVES AND ENDPOINTS ............................................................... 23 
4. 
STUDY DESIGN ......................................................................................... 23 
4.1 
Overall Design ....................................................................... 23 
4.1.1 
Dose-decision Criteria ........................................................... 24 
4.1.2 
Stopping Rules Criteria .......................................................... 25 
4.1.3 
Individual Stopping Rules ...................................................... 25 
4.1.4 
Communication Strategy ....................................................... 25 
4.1.5 
Length of the Study ............................................................... 26 
4.2 
Scientific Rationale for Study Design ..................................... 26 
4.2.1 
Rationale for Study Population .............................................. 26 
4.2.2 
Rationale for Pharmacokinetic Assessments ......................... 27 
4.3 
Justification for Dose ............................................................. 27 
4.3.1 
Risdiplam ............................................................................... 27 
4.3.2 
Midazolam ............................................................................. 27 
4.4 
End of Study Definition .......................................................... 28 


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Protocol BP41361, Version 1 
5. 
STUDY POPULATION ................................................................................ 28 
5.1 
Inclusion Criteria .................................................................... 28 
5.2 
Exclusion Criteria ................................................................... 29 
5.3 
Lifestyle Considerations ......................................................... 30 
5.3.1 
Meals and Dietary Restrictions .............................................. 30 
5.3.2 
Exercise ................................................................................. 31 
5.4 
Screen Failures ..................................................................... 31 
5.5 
Recruitment Procedures ........................................................ 32 
6. 
TREATMENTS ............................................................................................ 32 
6.1 
Treatments Administered ....................................................... 32 
6.2 
Preparation/Handling/Storage/Accountability ........................ 32 
6.3 
Measures to Minimize Bias: Randomization and 
Blinding .................................................................................. 34 
6.3.1 
Method of Treatment Assignment .......................................... 34 
6.3.2 
Blinding .................................................................................. 34 
6.4 
Treatment Compliance .......................................................... 34 
6.5 
Concomitant Therapy ............................................................ 34 
6.5.1 
Permitted Therapy ................................................................. 35 
6.5.2 
Prohibited Therapy ................................................................ 35 
6.6 
Dose Modification .................................................................. 36 
6.7 
Treatment after the End of the Study ..................................... 36 
7. 
DISCONTINUATION OF STUDY, STUDY TREATMENT, AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ................................. 36 
7.1 
Discontinuation of Study Treatment ....................................... 36 
7.2 
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 36 
7.3 
Lost to Follow-up ................................................................... 37 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................... 37 
8.1 
Efficacy Assessments ............................................................ 37 
8.2 
Safety Assessments .............................................................. 37 
8.2.1 
Physical Examinations ........................................................... 38 
8.2.2 
Vital Signs .............................................................................. 38 
8.2.3 
Electrocardiograms ................................................................ 38 


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Protocol BP41361, Version 1 
8.2.4 
Clinical Safety Laboratory Assessments................................ 39 
8.2.5 
Medical History and Demographic Data ................................ 39 
8.3 
Adverse Events and Serious Adverse Events ....................... 39 
8.3.1 
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event Information .......................... 40 
8.3.2 
Method of Detecting Adverse Events and Serious 
Adverse Events ........................................................................................ 41 
8.3.3 
Follow-up of Adverse Events and Serious 
Adverse Events ........................................................................................ 41 
8.3.3.1 Investigator Follow-up .......................................................... 41 
8.3.3.2 Sponsor Follow-up ............................................................... 41 
8.3.4 
Regulatory Reporting Requirements for Serious 
Adverse Events ........................................................................................ 41 
8.3.4.1 Emergency Medical Contacts ............................................... 42 
8.3.5 
Pregnancy ............................................................................. 42 
8.3.6 
Non-serious Adverse Events of Special Interest .................... 42 
8.3.7 
Disease-related Events and/or Disease-related 
Outcomes Not Qualifying as AEs or SAEs ............................................... 43 
8.3.8 
Management of Specific Adverse Events .............................. 43 
8.4 
Treatment of Overdose .......................................................... 43 
8.5 
Pharmacokinetics .................................................................. 43 
8.6 
Immunogenicity Assessments ............................................... 44 
8.7 
Pharmacodynamics and Biomarkers Analyses ...................... 44 
8.8 
Pharmacodynamics and Biomarker Samples ........................ 44 
8.9 
Samples for Research Biosample Repository ....................... 44 
8.10 
Health Economics OR Medical Resource 
Utilization ............................................................................... 44 
8.11 
Timing of Study Assessments ............................................... 44 
8.11.1 
Screening and Pre-treatment Assessments .......................... 44 
8.11.2 
Assessments During Treatment ............................................ 45 
8.11.3 
Assessments at Study Completion/Early 
Termination Visit ...................................................................................... 45 
8.11.4 
Follow-up Assessments ......................................................... 45 
9. 
STATISTICAL CONSIDERATIONS ............................................................ 45 
9.1 
Sample Size Determination ................................................... 45 


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Protocol BP41361, Version 1 
9.2 
Populations for Analyses ....................................................... 46 
9.3 
Statistical Analyses ................................................................ 46 
9.3.1 
Safety Analyses ..................................................................... 46 
9.3.2 
Pharmacokinetic Analyses ..................................................... 47 
9.4 
Interim Analyses .................................................................... 48 
9.5 
Summaries of Conduct of Study ............................................ 48 
10. REFERENCES ........................................................................................... 48 
 
 
 
 
LIST OF TABLES 
 
Table 1 
Schedule of Activities .................................................................. 14 
Table 2 
Objectives and Endpoints ........................................................... 23 
Table 3 
Summary of Treatments Administered ........................................ 32 
Table 4 
Analysis Populations ................................................................... 46 
Table 5 
Safety Statistical Analysis Methods ............................................ 46 
 
 
 
 
LIST OF APPENDICES 
 
Appendix 1 
 Regulatory, Ethical, and Study Oversight Considerations .......... 50 
Appendix 2 
 Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up, and Reporting ............................................................ 56 
Appendix 3 
 Procedures for Recording Adverse Events ................................ 63 
Appendix 4 
 Clinical Laboratory Tests ........................................................... 67 
Appendix 5 
 Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................. 69 


 
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Protocol BP41361, Version 1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ARAUC 
Accumulation ratio for AUC 
ARCmax 
Accumulation ratio for Cmax 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUCinf 
Area under the plasma concentration-time curve extrapolated to 
infinity 
AUClast 
Area under the plasma concentration-time curve from time 0 to 
the time of last quantifiable concentration 
AUCtau 
Area under the plasma concentration-time curve over a dosing 
interval 
BMI 
Body mass index 
CLss/F 
Apparent total plasma clearance at steady state 
Cmax 
Maximum observed plasma concentration 
CNS 
Central nervous system 
CRF 
Case Report Form 
Ctrough 
Trough observed plasma concentration 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Hepatitis B core antibody 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 


 
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Protocol BP41361, Version 1 
ICH 
International Conference for/Council on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
LPLV 
Last participant, last visit 
NSAESI 
Non-serious adverse event of special interest 
OTC 
Over-the-counter 
PK 
Pharmacokinetic(s) 
PR 
Pulse rate 
QD 
Once daily 
QRS 
QRS complex 
QT 
QT interval 
QTc 
QT corrected for heart rate 
QTcF 
QT corrected for heart rate using Fridericia’s formula 
RBC 
Red blood cell 
RR 
RR interval 
SAE 
Serious adverse event 
SMA 
Spinal muscular atrophy 
SMN 
Survival motor neuron 
SoA 
Schedule of Activities 
t½ 
Apparent plasma terminal elimination half-life 
Tmax 
Time of maximum observed plasma concentration 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of non-childbearing potential 


 
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Protocol BP41361, Version 1 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
A PHASE I, 2-PART, OPEN-LABEL STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF 
MULTIPLE DOSES OF RISDIPLAM AND THE EFFECT OF 
RISDIPLAM ON THE PHARMACOKINETICS OF MIDAZOLAM 
FOLLOWING ORAL ADMINISTRATION IN HEALTHY 
PARTICIPANTS 
SHORT TITLE: 
RISDIPLAM MULTIPLE DOSE AND MIDAZOLAM DRUG-DRUG 
INTERACTION STUDY 
PROTOCOL NUMBER: 
BP41361 
VERSION: 
1 
TEST PRODUCT: 
Risdiplam (RO7034067) 
PHASE: 
I 
 
RATIONALE 
Part 1 of this study will investigate the safety, tolerability, and pharmacokinetics (PK) of multiple 
oral doses of risdiplam administered once daily (QD) for 14 days to healthy participants. To 
date, risdiplam has not been investigated as a multiple-dose QD regimen in healthy participants; 
all previous Phase I studies have been single-dose studies. The PK and safety data collected in 
Part 1 will be used to define the dose and to enable the start of Part 2 of this study. 
 
Part 2 of this study will assess the effect of multiple oral doses of risdiplam on the PK of 
midazolam following administration to healthy participants, to check for drug-drug interaction of 
risdiplam with cytochrome P450 3A substrates. 
 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
To investigate the effect of multiple oral 
doses of risdiplam on the 
pharmacokinetics (PK) of a single oral 
dose of midazolam in healthy 
participants. 
Midazolam concentrations and thereof 
derived PK parameters for midazolam 
(and its metabolite[s] as appropriate) 
alone and in combination with risdiplam. 
Secondary 
To assess the safety and tolerability of a 
single oral dose of midazolam alone and 
in combination with multiple oral doses of 
risdiplam in healthy participants. 
 
Incidence and severity of adverse events 
(AEs); changes in vital signs, physical 
findings, electrocardiogram (ECG) 
parameters, and clinical laboratory test 
results during and after midazolam 
administration alone and in combination 
with risdiplam. 


 
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Protocol BP41361, Version 1 
To assess the safety and tolerability of 
multiple oral doses of risdiplam 
administered once daily (QD) for 14 days. 
Incidence and severity of AEs; changes in 
vital signs, physical findings, ECG 
parameters, and clinical laboratory test 
results during and after administration of 
multiple doses of risdiplam. 
To assess the PK of risdiplam (and its 
metabolite[s] as appropriate) following 
multiple oral doses of risdiplam QD for 
14 days. 
Concentrations and thereof derived PK 
parameters for risdiplam and its 
metabolite(s) as appropriate. 
 
OVERALL DESIGN 
Study Design 
This will be a Phase I, 2-part, open-label, non-randomized study to investigate the safety, 
tolerability, and PK of multiple doses of risdiplam (Part 1) and the effect of risdiplam on the PK 
of midazolam (Part 2) following oral administration in healthy adult male and female 
participants. 
 
Treatment Groups and Duration 
Study Treatment Name: 
Risdiplam (RO7034067) 
Midazolam (Part 2 only) 
Dose Formulation: 
Powder for constitution to an 
oral solution 
Solution 
Dose: 
5 mg (6.66 mL) (Part 1) 
2 mg (1 mL) 
Route of Administration: 
Oral 
Oral 
Note: The risdiplam dose for Part 2 will be defined based on Part 1 data. 
 
Length of Study 
The total duration of the study for each participant will be up to approximately 8 weeks divided 
as follows: 
• 
Screening: Up to 27 days (Days -28 to -2). 
• 
In clinic period: Day -1 to Day 16 (Part 1) or Day -1 to Day 18 (Part 2). 
• 
Non-residential visits: Days 18 and 20 (Part 1) or Days 20 and 22 (Part 2). 
• 
Safety Follow-up (Post-study): 10±2 days post final dose of study drug in Parts 1 and 2. 
 
End of Study 
The end of the study is defined as the date when the last participant last visit occurs. 
 
PARTICIPANT POPULATION 
The participants in this study will be healthy female and male volunteers between 18 and 
55 years of age, inclusive, who fulfill all of the given eligibility criteria. 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 
Willingness and ability to provide written consent to participate in the clinical trial. 
2. 
Healthy participants.  
Healthy status is defined by the Investigator based on detailed review of medical and surgical 
history, results of physical examination, vital signs, 12-lead ECG, and laboratory assessments 
(hematology, coagulation, blood chemistry, serology, and urinalysis). 
3. 
Male and female participants aged 18 to 55 years of age, inclusive, at Screening. 
a) Female participants: A female participant is eligible to participate if she is a woman of 
non-childbearing potential (WONCBP).  
4. 
A body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, at Screening. 


 
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Protocol BP41361, Version 1 
5. 
Use of adequate contraception methods during the treatment period and until 4 months 
after last study drug administration. Males must refrain from donating sperm during this 
same period.  
a) Contraception methods for male participants considered as acceptable for the study:  
o 
With non-pregnant female partners, use contraceptive measures such as a 
condom with spermicide plus an additional contraceptive method that together 
result in a failure rate of <1% per year, with partners who are women of 
childbearing potential. The additional contraceptive method must be 1 of the 
following: diaphragm in combination with spermicide, intrauterine device, 
injectable or implantable contraceptives, oral hormonal contraceptives (e.g., 
“progesterone only pills,” tablets, patch, or vaginal ring with both estrogen and 
progesterone). Contraception is required during the treatment period and for at 
least 4 months after the last dose of risdiplam. 
o 
With pregnant female partners, use contraceptive measures such as a condom 
to avoid exposing the embryo during the treatment period and for at least 
28 days after the last dose of risdiplam. 
Abstinence (including those who practice abstinence as part of their normal and preferred 
lifestyle, periodic abstinence, e.g., calendar, ovulation, symptothermal, or post ovulation 
methods) and withdrawal are not acceptable methods of contraception in this study. 
Note that only WONCBP and men are eligible for the study. 
6. 
Willingness and ability to complete all aspects of the study. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. 
History of any clinically significant GI, renal, hepatic, broncho-pulmonary, neurological, 
psychiatric, cardiovascular, endocrinological, hematological, or allergic disease, metabolic 
disorder, cancer, or cirrhosis. 
2. 
Concomitant disease or condition that could interfere with, or treatment of which might 
interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose 
an unacceptable risk to the participant in this study, including but not limited to the following: 
o 
Any major illness within 1 month before Screening or any febrile illness within 
1 week prior to Screening and up to first study drug administration. 
3. 
History or evidence of any medical condition potentially altering the absorption, metabolism, 
or elimination of drugs.  
4. 
Surgical history of the GI tract affecting gastric motility or altering the GI tract (with the 
exception of uncomplicated appendectomy and hernia repair) (a cholecystectomy is 
exclusionary). 
5. 
History or presence of clinically significant ECG abnormalities (based on the average of 
3 consecutive measurements [if the first measurement is out of range, complete 2 more and 
take the average]) (e.g., PQ/PR interval >210 ms, QT interval corrected for heart rate using 
Fridericia’s formula [QTcF] >450 ms for males and QTcF >470 ms for females) or 
cardiovascular disease (e.g., cardiac insufficiency, coronary artery disease, 
cardiomyopathy, congestive heart failure, family history of congenital long QT syndrome, 
family history of sudden death). 
6. 
History of malignancy in the past 5 years. 
7. 
Confirmed (based on the average of 3 consecutive measurements [if the first measurement 
is out of range, complete 2 more and take the average]) systolic blood pressure >140 or 
<90 mmHg, and diastolic blood pressure >90 or <50 mmHg at Screening only. 
8. 
Confirmed (based on the average of 3 consecutive measurements) resting pulse rate 
(PR) >100 or <40 bmp at Screening only. 
9. 
Clinically significant abnormalities (as judged by the Investigator) in laboratory test results 
(including hematology, chemistry panel, and urinalysis). In case of uncertain or 
questionable results, tests performed during Screening may be repeated on Day -1 to 
confirm eligibility. 


 
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Protocol BP41361, Version 1 
10. Positive result on human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B virus, or 
hepatitis C virus (serology) tests at Screening. 
11. Any suspicion or history of alcohol abuse and/or any history or suspicion of regular 
consumption/addiction of drugs of abuse within 2 years prior to study drug administration or 
a positive drug screen test as performed at Screening. 
12. Any consumption of tobacco-containing products (including but not limited to the following: 
smoking cigarettes, cigars, etc.) from 1 month before Screening until Follow-up. 
13. Donation of blood or blood products for transfusion over 500 mL within 3 months prior to 
first study drug administration and for the duration of the study. 
14. Participation in an investigational drug medicinal product or medical device study within 
90 days prior to Screening. 
15. Use of prohibited medications or herbal remedies. 
16. Any clinically significant history of hypersensitivity or allergic reactions, either spontaneous 
or following study drug administration, or exposure to food or environmental agents. 
17. History of hypersensitivity to any of the excipients in the formulation of the study drug. 
18. History of hypersensitivity to midazolam or any other benzodiazepine or its formulation 
ingredients (this applies to participants in Part 2 only). 
19. For Part 2 participants: history of acute angle glaucoma. 
20. Participants who, in the Investigator’s judgment, pose a suicidal risk, or any participant with 
a history of suicidal or homicidal attempts. 
21. Participants under judicial supervision, guardianship, or curatorship. 
22. Participants who, in the opinion of the Investigator, should not participate in this study. 
 
NUMBER OF PARTICIPANTS 
In total a maximum of 40 participants may be enrolled in this study as follows: 
• 
Part 1: 8 participants will be enrolled in order to obtain 6 evaluable participants. 
• 
Part 2: 28 participants will be enrolled in order to obtain at least 26 evaluable 
participants.  
The additional 4 participants are in case the dropout rate in Part 2 is higher than expected in 
order to achieve 26 evaluable participants. 
 
CONCOMITANT MEDICATIONS 
No concomitant medication is permitted, except acetaminophen, hormone replacement therapy 
for post-menopausal women, and medication to treat AEs. 
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
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 participant from 30 days prior to Screening until 
the Follow-up visit must be recorded along with reason for use, dates of administration 
(including start and end dates), and dosage information (including dose and frequency). 
Permitted Therapy 
Participants who use hormone replacement therapy should continue their use. 
Acetaminophen, at doses of ≤ 2 g/day, is permitted for use as needed. Other concomitant 
medication required to treat AEs may be considered on a case-by-case basis by the 
Investigator. 
Prohibited Therapy 
All medications (prescription and OTC) taken within 30 days of Screening will be recorded on 
the appropriate eCRF. 
As a general rule, no concomitant medication will be permitted, with the exception of 
acetaminophen, hormone replacement therapy for post-menopausal women, and medications 
to treat AEs, unless the rationale for exception is discussed and clearly documented between 
the Investigator and the Sponsor and archived in the site file. 


 
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Protocol BP41361, Version 1 
Participants must abstain from taking prescription or non-prescription drugs (including vitamins 
and dietary or herbal supplements) within 14 days or 5 half-lives (whichever is longer) before 
the start of study treatment until completion of the Follow-up visit, unless, in the opinion of the 
Investigator and Sponsor, the medication will not interfere with the study. 
The following medications are explicitly prohibited: 
• 
Any inhibitor of CYP3A4 (e.g., ketoconazole, miconazole, itraconazole, fluconazole, 
erythromycin, clarithromycin, ranitidine, cimetidine). 
• 
Any inducer of CYP3A4 (e.g., rifampicin, rifabutin, glucocorticoids, carbamazepine, 
phenytoin, phenobarbital, St. John’s wort). 
• 
Any organic cation transporter 2 and MATE substrates (e.g., amantadine, cimetidine, 
memantine, amiloride, famotidine, metformin, pindolol, ranitidine, procainamide, 
varenicline, acycolovir, ganciclovir, oxaliplatin, cephalexin, cephradine, fexofenadine). 
• 
Medications with known or potential retinal toxicity (e.g., chloroquine and 
hydroxychloroquine, thioridazine, retigabin, vigabatrin, desferoxamine, topiramate, 
latanoprost, niacin, rosiglitazone, tamoxifen, canthaxanthine, sildenafil, interferon, 
chronic use of minocycline). 
 
1.2 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities is provided in Table 1. 
 


 
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Table 1 
Schedule of Activities 
Part 1: 
 
Screening 
(Days -28 
to -2) 
Day -1 
Days 1 to 20 
Post-study 
(10±2 days post 
final dose)/Early 
Termination 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
 
 
 
Urine drugs of abuse screen (including cotinine) 
and alcohol test (refer to Appendix 4) 
X 
X 
 
 
Confirmation of non-childbearing potential 
(females only) (refer to Appendix 4) 
X 
 
 
 
Pregnancy test (females only) a (refer to 
Appendix 4) 
X 
X 
 
X 
Serology (refer to Appendix 4) 
X 
 
 
 
Study residency: 
 
 
 
 
Check-in 
 
X 
 
 
Check-out 
 
 
Day 16: Following 48-hour PK sample 
collection 
 
Non-residential visit 
X 
 
Day 18 and Day 20 
X 
Study drug administration: 
 
 
risdiplam: Days 1 to 14, once daily 
 
Safety and tolerability: 
 
 
 
 
Adverse event questioning 
 
X 
Ongoing 
X 
Vital signs (supine) b and 12-lead ECG 
X 
 
Day 1: Predose 
Day 7: Predose 
Day 14: Predose 
Day 16: 48 hours after last study drug 
administration 
X 
Clinical laboratory evaluations (refer to 
Appendix 4) 
X 
X 
Day 7: Predose 
Day 14: Predose 
Day 16: 48 hours after last study drug 
administration 
X 


 
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Screening 
(Days -28 
to -2) 
Day -1 
Days 1 to 20 
Post-study 
(10±2 days post 
final dose)/Early 
Termination 
Body weight, height, and BMI c 
X 
X 
 
 
Physical examination d 
X 
X 
 
X 
Pharmacokinetics: 
 
 
 
 
Blood sampling for risdiplam PK 
 
 
Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 
12 hours postdose 
Day 2 to Day 13: Predose 
Day 14: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 
24, 36, 48, 96, and 144 hours postdose 
 
Abbreviations: BMI = body mass index; ECG = electrocardiogram; PK = pharmacokinetic. 
a Performed in serum. 
b Systolic and diastolic blood pressure, pulse rate, and oral body temperature (oral body temperature at Screening and Day 1 predose only). 
c Height and BMI at Screening only. 
d Complete physical examination at Screening; brief physical examination thereafter. 
 
 
 


 
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Part 2: 
 
Screening 
(Days -28 
to -2) 
Day -1 
Days 1 to 22 
Post-study 
(10±2 days post 
final dose)/Early 
Termination 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
 
 
 
Urine drugs of abuse screen (including 
cotinine) and alcohol test (refer to 
Appendix 4) 
X 
X 
 
 
Confirmation of non-childbearing 
potential (females only) (refer to 
Appendix 4) 
X 
 
 
 
Pregnancy test (females only) a (refer to 
Appendix 4) 
X 
X 
 
X 
Serology (refer to Appendix 4) 
X 
 
 
 
Study residency: 
 
 
 
 
Check-in 
 
X 
 
 
Check-out 
 
 
Day 18: Following 48-hour risdiplam PK collection 
 
Non-residential visit 
X 
 
Day 20 and Day 22 
X 
Study drug administration: 
 
 
midazolam: Days 1 and 15 (administered 1 hour after the 
risdiplam dose on Day 15) 
risdiplam: Days 3 to 16 
 
Safety and tolerability: 
 
 
 
 
Adverse event questioning 
 
X 
Ongoing 
X 
Vital signs (supine) b and 12-lead ECG 
X 
 
Day 1: Predose, 1, 2, 4, and 6 hours postdose 
Day 3: Predose, 2, 4, 6, and 12 hours postdose 
Day 7: Predose 
Day 15: Predose, 1, 2, 4, and 6 hours postdose 
Day 16: Predose 
Day 18: 48 hours after last study drug administration 
Day 22 
X 


 
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Screening 
(Days -28 
to -2) 
Day -1 
Days 1 to 22 
Post-study 
(10±2 days post 
final dose)/Early 
Termination 
Clinical laboratory evaluations (refer to 
Appendix 4) 
X 
X 
Day 3: Predose 
Day 7: Predose 
Day 15: Predose 
Day 18: 48 hours after last study drug administration 
Day 22 
X 
Body weight, height, and BMI c 
X 
X 
 
 
Physical examination d 
X 
X 
 
X 
Pharmacokinetics: 
 
 
 
 
Blood sampling for midazolam PK 
 
 
 
Blood sampling for risdiplam PK 
 
 
Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 
12, and 24 hours postdose 
 
 
Day 3: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours 
postdose 
Day 4 to Day 15: Predose 
Day 16: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 
96, and 144 hours postdose 
 
Abbreviations: BMI = body mass index; ECG = electrocardiogram; PK = pharmacokinetic. 
Note: Nominal timepoints refer to the timepoint of risdiplam dose administration, with the exception of midazolam PK sampling and vital signs and 
ECG on Day 1, which refer to the timepoint of midazolam dose administration. The midazolam PK sample at 1 hour postdose corresponds to the 
same time of day as the risdiplam 2-hour postdose sample. 
a Performed in serum. 
b Systolic and diastolic blood pressure, pulse rate, and oral body temperature (oral body temperature at Screening and Day 1 predose only). 
c Height and BMI at Screening only. 
d Complete physical examination at Screening; brief physical examination thereafter. 
 


 
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2. 
INTRODUCTION 
Refer to the Investigator’s Brochure (IB)1 for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event 
(AE) profile of the investigational medicinal product (IMP). 
2.1 
OVERVIEW OF THE DISEASE 
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder 
characterized by the progressive loss of proximal motor neurons leading to muscle 
weakness beginning in infancy.2,3 It is the leading genetic cause of mortality in infants 
and young children, with an incidence of 1 in approximately 11,000 live births, and a 
carrier frequency estimated at between 1 in 50 and 1 in 70.4  
SMA is pathologically characterized by the degeneration of alpha motor neurons within 
the anterior horn of the spinal cord, leading to skeletal muscle weakness and atrophy. 
Muscle weakness and atrophy are symmetrical and progressive, often impacting the 
legs more than the arms, eventually leading to a decline in intercostal muscle strength. 
Respiratory failure and complications of orthopedic deformity account for the majority of 
deaths in patients with SMA.5  
SMA is caused by homozygous deletion (95% of cases) or mutation of the survival motor 
neuron (SMN)1 gene.6 In humans, there are 2 SMN genes (telomeric SMN1 gene and 
centromeric SMN2 gene), which originated from an intrachromosomal duplication of 
5q13 and subsequent divergence due to genetic drift. Species, other than humans, have 
only 1 SMN gene, which is equivalent to the human SMN1 gene. SMN2 differs from 
SMN1 by the presence of a translationally synonymous C→T mutation at nucleotide 6 in 
exon 7. As a result of this, the SMN2 pre-mRNA undergoes alternative splicing which 
excludes exon 7 from 85% to 90% of SMN2 transcripts, which produces an unstable 
SMN∆7 protein that is rapidly degraded.7 In the remaining 10% to 15% of splicing 
events, the full-length SMN2 mRNA is generated, leading to the production of functional 
full-length SMN protein. Accordingly, patients with SMA lacking a functioning SMN1 
gene are dependent on their SMN2 gene and SMA is the consequence of decreased, 
insufficient levels of full-length functional SMN protein which is produced only by the 
SMN2 gene.8  
2.2 
OVERVIEW OF RISDIPLAM 
There is currently no approved oral treatment that provides stabilization or improvement 
of motor function to patients with SMA. One of the promising strategies currently being 
pursued is to increase SMN protein levels in patients with SMA by modulating SMN2 
splicing to favor the inclusion of exon 7 into the mRNA transcript, thus increasing 
expression of stable full-length protein from the SMN2 gene.8,9 One such compound 
currently being developed is risdiplam (RO7034067), which directly targets the 
underlying molecular deficiency of SMA, to promote the inclusion of exon 7 to generate 
full-length SMN2 mRNA, increasing the production of functional SMN protein. The 


 
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increase in SMN protein following treatment with risdiplam has been shown in fibroblasts 
and motor neurons derived from patients with SMA, and in clinical trials in patients with 
SMA. 
2.2.1 
Summary of Clinical Experience 
The Phase I development of risdiplam comprised 3 completed studies in healthy 
subjects: a single-ascending dose study including an exploratory investigation of the 
effect of food and an itraconazole interaction part (Study BP29840), a study to 
investigate potential differences in the pharmacokinetic (PK) and safety and tolerability 
of risdiplam in healthy Japanese subjects compared with Caucasians (Study NP39625), 
and a mass balance study (Study BP39122). 
Currently, 3 clinical studies in patients with SMA are ongoing: a study in children and 
young adults with Type 2 and Type 3 SMA (Study BP39055) and in infants with Type 1 
SMA (Study BP39056), and an exploratory study in patients with SMA previously treated 
with another SMA therapy (Study BP39054). A study to assess the efficacy, safety and 
tolerability, and PK/pharmacodynamics of risdiplam in pre-symptomatic infants 
genetically diagnosed with SMA is in preparation. 
2.2.1.1 
Safety 
In Study BP29840, single doses of risdiplam administered alone at doses of 0.6 mg, 
2 mg, 6 mg, and 18 mg, or 6 mg in combination with itraconazole were well tolerated in 
healthy male subjects. There were no deaths, serious adverse events (SAEs), or 
withdrawals due to AEs. Overall, 27 AEs were reported, all of which were mild in 
intensity and resolved within a short period of time without sequelae. With the exception 
of 2 AEs (pollakiuria [placebo] and headache [18 mg risdiplam]), all events were 
considered by the Investigator to be unrelated to risdiplam. The most frequently affected 
system organ class was gastrointestinal (GI) disorders (9 AEs) and nervous system 
disorders (4 AEs). The most frequently reported AEs were headache (4 subjects) and 
diarrhea, abdominal pain, and nasopharyngitis (3 subjects each). There were no 
dose-related increases in the incidence or severity of reported AEs and no cluster of AEs 
indicative of a toxic effect of the compound on a given organ system. Although there 
were no safety findings at any dose administered, dose escalation was stopped at 
18 mg, as the protocol-specified plasma exposure cap of 1500 h.ng/mL for area under 
the plasma concentration-time curve (AUC) from time zero to 24 hours postdose on an 
individual basis for healthy subjects only was approached with this dose. 
Study NP39625 in healthy Japanese subjects demonstrated that single oral doses of 
risdiplam at 2 mg, 6 mg, and 12 mg were well tolerated with no marked differences in the 
safety profile between Japanese and Caucasian subjects. There were no SAEs, AEs 
leading to withdrawal from the study, or severe AEs reported. Overall, 12 AEs were 
reported, of which 10 were visual AEs reported in 6 subjects (visual acuity reduced in 
2 subjects who received placebo; bilateral cataracts and visual acuity reduced, and 
bilateral cataracts and vision blurred in 2 subjects who received 6 mg risdiplam; and 


 
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visual acuity reduced in 2 subjects who received 12 mg risdiplam). The events of visual 
acuity reduced in the placebo and 12 mg risdiplam groups and 1 of the bilateral cataract 
cases in the 6 mg risdiplam group were considered by the Investigator to be related to 
study treatment. However, the clinically trained ophthalmologist from the central reader 
Optic Nerve Research Center assessed that the findings were pre-existing cataracts that 
had worsened, which is in keeping with the natural history of the condition. No evidence 
was observed suggesting that the AEs of vision blurred or the worsened cataracts were 
related to the study medication. The Sponsor assessed the events as unrelated to study 
medication based on asymmetrical findings in both eyes, exposure to a single dose of 
study medication, no similar findings in other patients exposed to multiple doses (caveat 
higher age/Asian ethnicity), no findings in the previous healthy subject study with single 
ascending doses up to 18 mg (Study BP29840), no preclinical findings in lens, 
consideration that cataracts appear significantly earlier in Asians compared to 
Caucasians and therefore the study subject was at significant risk for cataract 
irrespective of study therapy. 
In Study BP39122, a single oral dose of 18 mg of [14C/12C]-risdiplam was well tolerated 
in healthy male subjects. All 6 subjects reported at least 1 AE, the most frequent being 
dry skin (3 subjects). There were no severe AEs or AEs leading to withdrawal from study 
treatment. One subject reported an SAE of pneumonia, which was assessed by the 
Investigator as unrelated to study treatment and resolved upon supportive treatment. 
In none of these studies were there any clinically significant treatment or 
dose-dependent changes compared with baseline in vital signs, electrocardiograms 
(ECGs), laboratory parameters, or ophthalmological assessments. 
Risdiplam has, so far, been well tolerated in the 3 currently ongoing clinical studies in 
patients with SMA, with a treatment duration of up to more than 1 year (with once daily 
[QD] administration). For further information, refer to the IB.1 
2.2.1.2 
Pharmacokinetics 
In the completed single-ascending dose study (including exploratory investigation of the 
effect of food and itraconazole interaction) in healthy adults (Study BP29840), risdiplam 
was rapidly absorbed with a median time of maximum observed plasma concentration 
(Tmax) between 2 and 3 hours postdose under fasted conditions. The maximum observed 
plasma concentration (Cmax) and AUC increased in a dose-proportional manner. The 
apparent plasma terminal elimination half-life (t½) was approximately 41 hours to 
64 hours. On average, a small fraction (<10%) of the administered dose was excreted 
unchanged into urine. Food had no relevant effect on the PK of risdiplam; only median 
Tmax was delayed to 4.5 hours postdose. Itraconazole had a minor effect on the PK of a 
single oral dose of risdiplam resulting in an increase (11%) of the AUC from time zero to 
120 hours postdose and a reduction (9%) of the Cmax. 


 
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A mass balance study (Study BP39122) with single-dose administration of 
[14C/12C]-risdiplam was conducted in healthy adult subjects. The mean overall recovery 
of total administered [14C]-radioactivity was 81.4%, ranging from 60.3% to 89.6%. The 
major pathway of elimination of [14C]-radioactivity was fecal excretion with, on average, 
53.2% of the dose administered; urinary excretion of [14C]-radioactivity accounted for, on 
average, 28.2% of the dose administered. 
Study NP39625 demonstrated no relevant differences in plasma or urine PK parameters, 
or the pharmacodynamic effects of risdiplam on SMN mRNA and SMN protein, between 
Japanese and Caucasian healthy subjects. 
M1 was confirmed as the major metabolite in patients with SMA, but it is not 
pharmacologically active. The median M1-to-parent ratio of all trough samples was 
approximately 30% with no apparent dose, time, body weight, or age dependency. 
2.3 
STUDY RATIONALE 
This study will assess the effect of risdiplam on the PK of the sensitive cytochrome P450 
(CYP)3A substrate midazolam, as measured by midazolam systemic exposure. 
An in vitro signal for time-dependent inhibition of CYP3A by risdiplam has been identified 
recently. The assessment of time-dependent inhibition in vivo requires multiple-dose 
administration of risdiplam for 2 weeks as QD dosing. To date, however, risdiplam has 
not been investigated as a multiple-dose regimen in healthy participants; all previous 
Phase I studies have been single-dose studies. Therefore, Part 1 of this study will 
investigate the safety, tolerability, and PK of multiple oral doses of risdiplam 
administered QD for 14 days to healthy participants. After review of Part 1 data, Part 2 of 
the study will begin. 
Part 2 of this study will assess the effect of multiple doses of risdiplam on the PK of 
midazolam following oral administration to healthy participants, to check for drug-drug 
interaction (DDI) of risdiplam with CYP3A substrates. 
The rationale for the study design is provided in Section 4.2. 
2.4 
BACKGROUND 
2.4.1 
Background on Risdiplam 
Refer to Section 2.1 for an overview of the disease SMA and to Section 2.2 for an 
overview of risdiplam. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of risdiplam is 
provided in the IB.1 


 
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2.4.2 
Background on Midazolam 
Midazolam is a short-acting benzodiazepine. Midazolam is the paradigm marker 
substrate for the in vivo assessment of CYP3A activity recommended by the Food and 
Drug Administration (FDA) and European Medicines Agency (EMA).10  
Midazolam is rapidly absorbed after oral administration and is subject to substantial 
intestinal and hepatic first-pass metabolism. Midazolam is primarily metabolized in the 
liver and gut by human CYP3A to its pharmacologically active metabolite 
1-OH-midazolam. In the subsequent UDP-glucuronosyltransferase-mediated phase II-
reaction, the main urinary metabolite 1’-OH-midazolam-glucuronide is formed; 63% to 
80% of the dose is found conjugated in the urine within 24 hours, while only 1% is 
excreted unchanged. The mean t½ of midazolam ranges from 2.2 to 6.8 hours following 
single oral dose administration. 
The PK interactions with CYP3A inhibitors or inducers are of higher magnitude on oral 
administration of midazolam compared to intravenous administration, particularly 
because CYP3A is also present in the upper GI tract. The reason for this is that by the 
oral administration route, both systemic clearance and bioavailability are subject to 
change, while by the parenteral administration route, only the systemic clearance will be 
affected. 
Pharmacodynamic properties of midazolam and its metabolites include sedative, 
anxiolytic, amnesic, and hypnotic activities. Benzodiazepine pharmacological effects 
appear to result from reversible interactions with the γ-amino butyric acid 
benzodiazepine receptor in the central nervous system (CNS), the major inhibitory 
neurotransmitter in the CNS.11 
An oral dose of 2 mg of midazolam will be used in this study.  
2.5 
BENEFIT/RISK ASSESSMENT 
Participants in the current study will not receive any health benefit (beyond that of an 
assessment of their medical status) from participating in the study. The risks of 
participation are primarily those associated with adverse reactions to the study 
treatments, although there may also be some discomfort from collection of blood 
samples and other study procedures. However, the potential risks for any participant due 
to the treatment with risdiplam, midazolam (applicable to patients enrolled in Part 2 
only), or study-related procedures are considered minimal and are outweighed by the 
opportunity for developing a new oral treatment for SMA.  
To minimize any potential risk, participants will be carefully selected in line with eligibility 
criteria and closely monitored for safety and will be under continuous medical 
observation during the course of the study. 


 
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Single doses of up to 18 mg risdiplam were well tolerated in healthy participants 
previously, and patients with SMA have received doses of up to 5 mg risdiplam QD for 
more than 1 year without any obvious drug-related safety signals. 
More detailed information about the potential risks associated with administration of 
risdiplam is provided in the IB.1 
3. 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints are provided in Table 2. 
Table 2 
Objectives and Endpoints
Objectives 
Endpoints 
Primary 
To investigate the effect of multiple 
oral doses of risdiplam on the 
pharmacokinetics (PK) of a single 
oral dose of midazolam in healthy 
participants. 
Midazolam concentrations and thereof derived PK 
parameters for midazolam (and its 
metabolite[s] as appropriate) alone and in 
combination with risdiplam. 
Secondary 
To assess the safety and tolerability of 
a single oral dose of midazolam 
alone and in combination with 
multiple oral doses of risdiplam in 
healthy participants. 
 
Incidence and severity of adverse events (AEs); 
changes in vital signs, physical findings, 
electrocardiogram (ECG) parameters, and 
clinical laboratory test results during and after 
midazolam administration alone and in 
combination with risdiplam. 
To assess the safety and tolerability of 
multiple oral doses of risdiplam 
administered once daily (QD) for 
14 days. 
Incidence and severity of AEs; changes in vital 
signs, physical findings, ECG parameters, and 
clinical laboratory test results during and after 
administration of multiple doses of risdiplam. 
To assess the PK of risdiplam (and its 
metabolite[s] as appropriate) 
following multiple oral doses of 
risdiplam QD for 14 days. 
Concentrations and thereof derived PK parameters 
for risdiplam and its metabolite(s) as 
appropriate. 
 
4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This will be a Phase I, 2-part, open-label, non-randomized study to investigate the 
safety, tolerability, and PK of a multiple-dosing regimen of risdiplam (QD; Part 1) and the 
effect of risdiplam on the PK of midazolam (Part 2) following oral administration in 
healthy adult male and female participants.  


 
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In total a maximum of 40 participants may be enrolled in this study as follows: 
• 
Part 1: 8 participants will be enrolled in order to obtain at least 6 evaluable 
participants.  
• 
Part 2: 28 participants will be enrolled in order to obtain at least 26 evaluable 
participants.  
The additional 4 participants are in case the dropout rate in Part 2 is higher than 
expected in order to achieve 26 evaluable participants. Participants enrolled in Part 1 of 
this study must not be enrolled in Part 2. 
In Part 1, participants will receive a dose of 5 mg risdiplam QD for 14 consecutive days. 
The dose of 5 mg risdiplam has been shown to be safe and well tolerated for more than 
1 year of treatment in patients with SMA. The decision to proceed to Part 2 of the study 
will be made following review of all available safety and tolerability data, including AEs, 
ECGs, vital signs, laboratory safety test results (i.e., hematology, clinical chemistry, and 
urinalysis) collected up to (and including) 48 hours after last study drug administration 
and available plasma PK data up to (and including) 24 hours after last study drug 
administration from a minimum of 4 Part 1 participants. The risdiplam dose in Part 2 will 
be determined based on the PK and safety data obtained in Part 1, with the aim to 
achieve an average exposure (mean AUC over a dosing interval [AUCtau] at steady 
state) of 2000 ng.h/mL in Part 2 (i.e., the therapeutic exposure observed in SMA 
patients). 
A Dose Escalation Meeting will be conducted prior to the start of Part 2 (see 
Section 4.1.1), in order to evaluate the Part 1 data and to select the risdiplam dose to be 
administered in Part 2 of this study. 
In Part 2, all study participants will receive a single oral dose of 2 mg midazolam on 
Day 1. On Day 3, the 14-day QD treatment period with risdiplam will begin (targeting a 
mean AUCtau at steady state of 2000 ng.h/mL; the precise dose will be based on the 
results of Part 1), with single dose administration of 2 mg midazolam again on Day 15 
(1 hour after the thirteenth dose of risdiplam). 
In both study parts, PK blood samples will be collected at timepoints specified in Table 1. 
Safety monitoring will be performed throughout the study as described in Section 8.2. 
The Schedule of Activities (SoA) for Parts 1 and 2 is provided in Table 1. 
4.1.1 
Dose-decision Criteria 
The decision to proceed to Part 2 will be made following review of all safety and 
tolerability information collected up to 48 hours after last study drug administration 
(including AEs, ECGs, vital signs, and clinical laboratory test results), and of all PK data 
collected up to (and including) 24 hours after last study drug administration in Part 1 
from a minimum of 4 participants. The dose of risdiplam to be administered in Part 2 will 
be selected to target a mean AUCtau at steady state of 2000 ng.h/mL (the therapeutic 


 
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exposure observed in patients with SMA). The dose to be administered in Part 2 may 
only be greater than in Part 1 if the dose of 5 mg of risdiplam tested in Part 1 was safe 
and well tolerated and stopping rules were not met.  
The decision to proceed to Part 2 will be made jointly by the Sponsor Clinical 
Pharmacologist and the Investigator and any other person(s) they consider necessary to 
assist with the decision. 
The maximum possible dose for Part 2 is 18 mg of risdiplam, and this dose will not be 
exceeded under any circumstances. 
4.1.2 
Stopping Rules Criteria 
The dose of risdiplam in Part 2 will not be increased beyond 5 mg, if 1 of the following 
circumstances occurs in participants treated with 5 mg risdiplam in Part 1, unless it is 
obvious that the occurrence is not related to the administration of risdiplam. 
• 
Severe AEs of the same type in ≥ 50% of participants. 
• 
Clinically significant laboratory abnormalities of the same type in ≥ 50% of 
participants. 
• 
Clinically significant changes in ECGs of the same type in ≥ 50% participants. 
• 
Other findings, which at the joint discretion of the Sponsor Clinical Pharmacologist 
and the Investigator, indicate that the dose in Part 2 should not be increased. 
 
4.1.3 
Individual Stopping Rules  
Dosing will be stopped in a given individual participant if, compared to baseline (as 
applicable), 1 of the following circumstances occurs, unless it is obvious that the 
occurrence is not related to the administration of risdiplam: 
• 
An SAE. 
• 
Any elevation of alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN), 
with an associated increase in bilirubin > 2 x ULN, and with aspartate 
aminotransferase (AST) < 2 x ULN, in the absence of an alternative explanation. 
• 
Other findings that, at the joint discretion of the Sponsor Clinical Pharmacologist and 
the Investigator, indicate that dosing should be stopped. 
 
4.1.4 
Communication Strategy 
In Part 1, there will be an ongoing review of available data. A dose-decision meeting will 
be conducted between the Sponsor study team and the Investigator prior to start of 
Part 2. 
 


 
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4.1.5 
Length of the Study 
The total duration of the study for each participant will be up to approximately 8 weeks 
divided as follows: 
• 
Screening: Up to 27 days (Days -28 to -2). 
• 
In clinic period: Day -1 to Day 16 (Part 1) or Day -1 to Day 18 (Part 2). 
• 
Non-residential visits: Days 18 and 20 (Part 1) or Days 20 and 22 (Part 2). 
• 
Safety Follow-up (Post-study): 10±2 days post final dose of study drug in Parts 1 
and 2. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The study rationale is provided in Section 2.3. 
An in vitro signal for time-dependent inhibition of CYP3A by risdiplam has been identified 
recently. The assessment of time-dependent inhibition in vivo requires multiple-dose 
administration of risdiplam for 2 weeks QD dosing. Since risdiplam has not yet been 
tested as a multiple-dosing regimen in healthy participants, in Part 1 the safety, 
tolerability, and PK of multiple oral doses of 5 mg risdiplam QD for 14 consecutive days 
will be assessed. The information gained in Part 1 will inform the dose selection for Part 
2, in which the effect of multiple doses of risdiplam on the PK of the sensitive CYP3A 
substrate midazolam will be assessed, at a risdiplam dose targeting a mean AUCtau at 
steady state of 2000 h.ng/mL, which is the therapeutic exposure observed in SMA 
patients. 
The seamless transition between the 2 parts and the adaptive nature of the study will 
allow for effective use of emerging data across the 2 parts of the study, while ensuring 
the safety of the participants through strict dose decision rules. In order to ensure 
maximum safety and tolerability, the effects of the dose in Part 1 will be reviewed 
carefully before starting Part 2. Part 2 will take place after the review of safety, 
tolerability, and PK data as described in Section 4.1.1. 
In Part 2, the effect of multiple oral doses of risdiplam (QD) on the PK of midazolam, a 
substrate specific for the drug-metabolizing CYP isozyme CYP3A, will be explored. The 
dose of risdiplam in Part 2 will be selected based on all available data from a minimum 
of 4 participants from Part 1. 
4.2.1 
Rationale for Study Population 
Healthy male participants and female participants of non-childbearing potential aged 
18 to 55 years (inclusive) were chosen because of the absence of potentially 
confounding disease processes, which will lead to a clearer and more consistent 
assessment of drug safety, tolerability, and pharmacological activity. Healthy participants 
are unlikely to require concomitant medication which could have an impact on the PK of 


 
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risdiplam and/or midazolam, respectively, or on the assessment of a potential DDI 
between these 2 compounds, which is the primary objective of this study. 
4.2.2 
Rationale for Pharmacokinetic Assessments 
Pharmacokinetic assessment of risdiplam and midazolam concentrations, and their 
metabolite(s) if appropriate, in plasma are included in the study. The times of PK sample 
collection are based on previous studies and are considered adequate to allow 
characterization of the drug’s PK after oral dosing. Furthermore, sample collection up to 
144 hours postdose for risdiplam and up to 24 hours postdose for midazolam is 
anticipated to be sufficient to allow reasonable estimation of half-life during the terminal 
elimination phase. 
4.3 
JUSTIFICATION FOR DOSE 
4.3.1 
Risdiplam 
Safety data of risdiplam in healthy subjects from the dedicated clinical pharmacology 
studies (BP29840, BP39122, and NP39625) demonstrated that single oral doses of 
risdiplam up to 18 mg have been safe and well tolerated in healthy subjects without 
relevant safety concerns. Treatment with risdiplam up to 5 mg QD for more than 1 year 
has been safe and well tolerated in patients with SMA in the currently ongoing clinical 
studies. Further details are provided in the IB.1 The dose of 5 mg risdiplam is the 
therapeutic dose administered to adult patients with SMA in the ongoing pivotal trials to 
evaluate the safety and efficacy of risdiplam. The exposure observed at this dose is a 
mean AUCtau at steady state of 2000 ng.h/mL. In order to evaluate the potential for DDI, 
the dose administered in Part 2 will therefore target a mean AUCtau at steady state of 
2000 ng.h/mL. 
The duration of risdiplam dosing of 14 days is required, and is considered to be 
sufficient, to evaluate the potential for time-dependent inhibition of CYP3A by risdiplam. 
4.3.2 
Midazolam 
Midazolam is a short-acting benzodiazepine. It has been selected because it is 
exclusively metabolized by CYP3A, is not a substrate of P-glycoprotein, and it has been 
validated in a number of studies as a CYP3A substrate. It is recommended as the 
sensitive model substrate for CYP3A by regulatory agencies (e.g., the FDA and EMA) 
and is the most widely used CYP3A probe substrate.12 As the majority of co-medication 
in the targeted patient population is administered by the oral route, the oral 
administration of midazolam has been selected, which will reveal the effect of possible 
inhibition of intestinal and liver CYP3A. 
A midazolam dose of 2 mg has been selected for Part 2 of this study because this dose 
is expected to yield midazolam plasma concentrations sufficient to adequately capture 
midazolam PK outcomes. 


 
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4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if they have completed all 
portions of the study including the last scheduled procedure shown in the SoA 
(Section 1.2). 
The end of the study is defined as the date when the last participant last visit (LPLV) 
occurs. 
5. 
STUDY POPULATION 
The study population rationale is provided in Section 4.2.1. 
The participants in this study will be healthy male and female of non-childbearing 
potential volunteers between 18 and 55 years of age, inclusive, who fulfill all of the given 
eligibility criteria. 
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
23. Willingness and ability to provide written consent to participate in the clinical trial. 
24. Healthy participants.  
Healthy status is defined by the Investigator based on detailed review of medical 
and surgical history, results of physical examination, vital signs, 12-lead ECG, and 
laboratory assessments (hematology, coagulation, blood chemistry, serology, and 
urinalysis). 
25. Male and female participants aged 18 to 55 years of age, inclusive, at Screening. 
a) Female participants: A female participant is eligible to participate if she is a 
woman of non-childbearing potential (WONCBP; as defined in Section 1 of 
Appendix 5).  
26. A body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, at Screening. 
27. Use of adequate contraception methods during the treatment period and until 
4 months after last study drug administration. Males must refrain from donating 
sperm during this same period.  
a) Contraception methods for male participants considered as acceptable for the 
study:  
o With non-pregnant female partners, use contraceptive measures such as 
a condom with spermicide plus an additional contraceptive method that 
together result in a failure rate of <1% per year, with partners who are 
women of childbearing potential (as defined in Section 1 of Appendix 5). 


 
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The additional contraceptive method must be 1 of the following: 
diaphragm in combination with spermicide, intrauterine device, injectable 
or implantable contraceptives, oral hormonal contraceptives (e.g., 
“progesterone only pills,” tablets, patch, or vaginal ring with both estrogen 
and progesterone). Contraception is required during the treatment period 
and for at least 4 months after the last dose of risdiplam. 
o With pregnant female partners, use contraceptive measures such as a 
condom to avoid exposing the embryo during the treatment period and for 
at least 28 days after the last dose of risdiplam. 
Abstinence (including those who practice abstinence as part of their normal and 
preferred lifestyle, periodic abstinence, e.g., calendar, ovulation, symptothermal, or 
post ovulation methods) and withdrawal are not acceptable methods of 
contraception in this study. 
Note that only WONCBP and men are eligible for the study (see Appendix 5). 
28. Willingness and ability to complete all aspects of the study. 
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
29. History of any clinically significant GI, renal, hepatic, broncho-pulmonary, 
neurological, psychiatric, cardiovascular, endocrinological, hematological, or allergic 
disease, metabolic disorder, cancer (refer to Exclusion Criterion 6), or cirrhosis. 
30. Concomitant disease or condition that could interfere with, or treatment of which 
might interfere with, the conduct of the study, or that would, in the opinion of the 
Investigator, pose an unacceptable risk to the participant in this study, including but 
not limited to the following: 
o Any major illness within 1 month before Screening or any febrile illness 
within 1 week prior to Screening and up to first study drug administration. 
31. History or evidence of any medical condition potentially altering the absorption, 
metabolism, or elimination of drugs.  
32. Surgical history of the GI tract affecting gastric motility or altering the GI tract (with 
the exception of uncomplicated appendectomy and hernia repair) (a 
cholecystectomy is exclusionary). 
33. History or presence of clinically significant ECG abnormalities (based on the 
average of 3 consecutive measurements [if the first measurement is out of range, 
complete 2 more and take the average]) (e.g., PQ/PR interval >210 ms, QT interval 
corrected for heart rate using Fridericia’s formula [QTcF] >450 ms for males and 
QTcF >470 ms for females) or cardiovascular disease (e.g., cardiac insufficiency, 
coronary artery disease, cardiomyopathy, congestive heart failure, family history of 
congenital long QT syndrome, family history of sudden death). 
34. History of malignancy in the past 5 years. 
35. Confirmed (based on the average of 3 consecutive measurements [if the first 
measurement is out of range, complete 2 more and take the average]) systolic blood 


 
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pressure >140 or <90 mmHg, and diastolic blood pressure >90 or <50 mmHg at 
Screening only. 
36. Confirmed (based on the average of 3 consecutive measurements) resting pulse 
rate (PR) >100 or <40 bmp at Screening only. 
37. Clinically significant abnormalities (as judged by the Investigator) in laboratory test 
results (including hematology, chemistry panel, and urinalysis). In case of uncertain 
or questionable results, tests performed during Screening may be repeated on 
Day -1 to confirm eligibility. 
38. Positive result on human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B virus, or 
hepatitis C virus (serology; see Appendix 4) tests at Screening. 
39. Any suspicion or history of alcohol abuse and/or any history or suspicion of regular 
consumption/addiction of drugs of abuse within 2 years prior to study drug 
administration or a positive drug screen test as performed at Screening. 
40. Any consumption of tobacco-containing products (including but not limited to the 
following: smoking cigarettes, cigars, etc.) from 1 month before Screening until 
Follow-up. 
41. Donation of blood or blood products for transfusion over 500 mL within 3 months 
prior to first study drug administration and for the duration of the study. 
42. Participation in an investigational drug medicinal product or medical device study 
within 90 days prior to Screening. 
43. Use of prohibited medications or herbal remedies (see Section 6.5.2). 
44. Any clinically significant history of hypersensitivity or allergic reactions, either 
spontaneous or following study drug administration, or exposure to food or 
environmental agents. 
45. History of hypersensitivity to any of the excipients in the formulation of the study 
drug. 
46. History of hypersensitivity to midazolam or any other benzodiazepine or its 
formulation ingredients (this applies to participants in Part 2 only). 
47. For Part 2 participants: history of acute angle glaucoma. 
48. Participants who, in the Investigator’s judgment, pose a suicidal risk, or any 
participant with a history of suicidal or homicidal attempts. 
49. Participants under judicial supervision, guardianship, or curatorship. 
50. Participants who, in the opinion of the Investigator, should not participate in this 
study. 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 
Meals and Dietary Restrictions 
While confined at the Clinical Research Unit, participants will receive a standardized diet 
at scheduled times that do not conflict with other study-related activities. Participants will 
be fasted overnight (at least 8 hours) before collection of blood samples for clinical 
laboratory evaluations. 


 
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Participants will be fasted overnight (at least 8 hours) prior to dosing on Day 1 (Part 1) 
and on Days 1, 3, and 15 (Part 2) and will refrain from consuming water from 1 hour 
predose until 2 hours postdose, excluding the amount of water consumed at dosing. 
Food is allowed from 4 hours postdose. At all other times during the study, participants 
may consume water ad libitum. 
Foods and beverages containing poppy seeds will not be allowed from 7 days prior to 
Check-in (Day -1) and throughout the study (until after the Follow-up visit). 
Foods and beverages containing grapefruit/grapefruit juice or Seville oranges will not be 
allowed from 14 days prior to study drug administration (Day 1) and throughout the study 
(until after the Follow-up visit). 
Caffeine-containing foods and beverages will not be allowed from 48 hours before 
Check-in (Day -1) until discharge on Day 14. 
Consumption of alcohol will not be permitted from 48 hours prior to Check-in (Day -1) 
until the Follow-up visit. 
5.3.2 
Exercise 
Participants are required to refrain from strenuous exercise from 7 days before Check-in 
(Day -1) until the Follow-up visit and will otherwise maintain their normal level of physical 
activity during this time (i.e., will not begin a new exercise program nor participate in any 
unusually strenuous physical exertion). 
Participants may participate in light recreational activities during studies (e.g., watching 
television, reading). 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study 
but do not fulfill all of the eligibility criteria and are not subsequently progressing in the 
study. 
The Investigator will maintain a screening log to record details of all consented/screened 
participants. The log will provide confirmation of eligibility or reason for failure for all 
participants at the site. 
Individuals who do not meet the criteria for participation in this study (screen failure) will 
not be re-screened unless agreed with the Sponsor. A repeat of a screening laboratory 
test because of a borderline result is not considered a re-screening and can be done 
only once at Day -1.  


 
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5.5 
RECRUITMENT PROCEDURES 
Participants will be identified for potential recruitment using pre-screening enrollment 
logs, clinical database and/or Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC) approved newspaper/radio/social-media advertisements prior to 
consenting to take place in this study. 
6. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol. 
The IMP for this study is risdiplam. Midazolam is a non-IMP for this study. Risdiplam will 
be provided by the Sponsor. Midazolam will be sourced locally by the trial site. All study 
drug administration will occur at the study center under supervision of medically qualified 
site staff. 
6.1 
TREATMENTS ADMINISTERED 
Table 3 summarizes the treatments administered. 
Table 3 
Summary of Treatments Administered 
Study Treatment 
Name: 
Risdiplam (RO7034067) 
Midazolam 
(Part 2 only) 
Dose 
Formulation: 
Powder for constitution to an oral solution 
Solution 
Unit Dose 
Strength: 
Each bottle contains 60 mg of risdiplam substance 
with excipients. The powder is constituted with purified 
water to yield an oral solution containing 0.75 mg/mL 
of risdiplam. 
2 mg/mL 
Dose: 
5 mg (6.66 mL) (Part 1) 
Dose for Part 2 to be determined based on Part 1 data 
2 mg (1 mL) 
Route of 
Administration: 
Oral 
Oral 
Sourcing: 
Provided centrally by the Sponsor 
Provided locally 
by the trial site 
 
See the local prescribing information for more details on midazolam. 
See the IB and Pharmacy Manual for more details on risdiplam. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and contain a label with the identification required by local law, the protocol number, 
drug identification, and dosage. 


 
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The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations. 
The investigational site will acknowledge receipt of IMP and confirm the shipment 
condition and content. Any damaged shipments will be replaced. 
Upon arrival of the IMP at the site, site personnel will complete the following: 
• 
Check the IMP for damage. 
• 
Verify proper identity, quantity, integrity of seals, and temperature conditions. 
• 
Report any deviations or product complaints to the Study Monitor upon discovery. 
 
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the treatment assignment schedule/Pharmacy Manual. 
The Investigator or delegate must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. Any temperature excursions during storage should be reported 
to the Sponsor immediately. Affected IMP cannot be administered until permission is 
granted by the Sponsor. 
The Investigator is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
Investigational medicinal products 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 IMP for safety reasons. The site must obtain written authorization 
from the Sponsor before any IMP is destroyed, and IMP destruction must be 
documented on the appropriate form. 
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual. 


 
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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING 
6.3.1 
Method of Treatment Assignment 
This is a non-randomized study and has a fixed treatment sequence.  
The study will use objective PK endpoints, and therefore no bias is anticipated.  
Assignment of participant numbers will be in ascending order and no numbers will be 
omitted. Participants will be dosed in numerical order. 
6.3.2 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
6.4 
TREATMENT COMPLIANCE 
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the treatment schedule. This individual will write the date 
dispensed and participant number on the study treatment bottle label and on the Drug 
Accountability Record. This individual will also record the study treatment number 
received by each participant during the study. The number will be noted for the IMP; for 
participants in Part 2, midazolam accountability will be done separately. 
The following measures will be employed to ensure treatment compliance: 
• 
All doses will be administered under the supervision of suitably qualified study site 
staff. 
• 
Immediately after dose administration, visual inspection of the mouth will be 
performed for each participant. 
• 
A predose and postdose inventory of IMP will be performed. 
 
6.5 
CONCOMITANT THERAPY 
No concomitant medication is permitted, except acetaminophen, hormone replacement 
therapy for post-menopausal women, and medication to treat AEs. 
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
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 participant 
from 30 days prior to Screening until the Follow-up visit must be recorded along with 
reason for use, dates of administration (including start and end dates), and dosage 
information (including dose and frequency). 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. Such consultation should be adequately documented and 
archived in the site file. 


 
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All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF). 
All therapy and/or medication administered to manage AEs should be recorded on the 
Adverse Event eCRF. 
6.5.1 
Permitted Therapy 
Participants who use hormone replacement therapy should continue their use. 
Acetaminophen, at doses of ≤ 2 g/day, is permitted for use as needed. Other 
concomitant medication required to treat AEs may be considered on a case-by-case 
basis by the Investigator. 
6.5.2 
Prohibited Therapy 
All medications (prescription and OTC) taken within 30 days of Screening will be 
recorded on the appropriate eCRF. 
As a general rule, no concomitant medication will be permitted, with the exception of 
acetaminophen, hormone replacement therapy for post-menopausal women, and 
medications to treat AEs, unless the rationale for exception is discussed and clearly 
documented between the Investigator and the Sponsor and archived in the site file. 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 14 days or 5 half-lives (whichever is 
longer) before the start of study treatment until completion of the Follow-up visit, unless, 
in the opinion of the Investigator and Sponsor, the medication will not interfere with the 
study. 
The following medications are explicitly prohibited: 
• 
Any inhibitor of CYP3A4 (e.g., ketoconazole, miconazole, itraconazole, fluconazole, 
erythromycin, clarithromycin, ranitidine, cimetidine). 
• 
Any inducer of CYP3A4 (e.g., rifampicin, rifabutin, glucocorticoids, carbamazepine, 
phenytoin, phenobarbital, St. John’s wort). 
• 
Any organic cation transporter 2 and MATE substrates (e.g., amantadine, 
cimetidine, memantine, amiloride, famotidine, metformin, pindolol, ranitidine, 
procainamide, varenicline, acycolovir, ganciclovir, oxaliplatin, cephalexin, 
cephradine, fexofenadine). 
• 
Medications with known or potential retinal toxicity (e.g., chloroquine and 
hydroxychloroquine, thioridazine, retigabin, vigabatrin, desferoxamine, topiramate, 
latanoprost, niacin, rosiglitazone, tamoxifen, canthaxanthine, sildenafil, interferon, 
chronic use of minocycline). 
 


 
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6.6 
DOSE MODIFICATION 
Not applicable. 
6.7 
TREATMENT AFTER THE END OF THE STUDY 
Not applicable. 
7. 
DISCONTINUATION OF STUDY, STUDY TREATMENT, AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Details on study and site closures are provided in Appendix 1. 
7.1 
DISCONTINUATION OF STUDY TREATMENT 
See the SoA (Section 1.2) for data to be collected at the time of treatment 
discontinuation/Early Termination and Follow-up and for any further evaluations that 
need to be completed. 
Every effort should be made to obtain information on participants who withdraw from the 
study but have not withdrawn consent. Participants who discontinue study treatment 
prematurely will be asked to return to the clinic for a Study Completion/Early Termination 
visit (see Section 8.11.3) and may undergo follow-up assessments (see Section 8.11.4), 
unless the participant withdrew consent. The primary reason for premature study 
treatment discontinuation should be documented on the appropriate eCRF. Participants 
who discontinue study treatment prematurely may be replaced depending on the reason 
for discontinuation, as defined in Section 7.2 below. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY 
Participants have the right to voluntarily withdraw from the study at any time for any 
reason. 
In addition, the Investigator has the right to withdraw a participant from the study for 
medical conditions that the Investigator or Sponsor determines may jeopardize the 
participant’s safety if he/she continues in the study. 
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn. 
When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will be used as part of the overall research data. 


 
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Participants who withdraw from the study for safety reasons will not be replaced. 
Participants who withdraw from the study for other reasons may be replaced at the joint 
discretion of the Investigator and the Sponsor Clinical Pharmacologist. 
See the SoA (Section 1.2) for data to be collected at the time of study discontinuation. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the study. 
Discontinuation of sites or of study as a whole are handled as part of Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timepoints are summarized in the SoA (Section 1.2). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. Such consultation should be adequately documented and archived in 
the site file. 
The maximum amount of blood collected from each participant will not exceed 500 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1 
EFFICACY ASSESSMENTS 
Not applicable. 
8.2 
SAFETY ASSESSMENTS 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.2). 


 
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Safety assessments will consist of monitoring and recording AEs, including SAEs and 
AEs of special interest (AESIs); measurement of protocol-specified safety laboratory 
assessments, vital signs, and ECGs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study. 
8.2.1 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, GI, dermatological, and musculoskeletal systems in 
addition to the head, eyes, ears, nose, throat, neck, and lymph nodes. Height, 
weight, and BMI will also be calculated and recorded at specified times. Further 
examination of other body systems may be performed in case of evocative 
symptoms at the Investigator’s discretion. 
• 
A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
The physical exam will NOT include pelvic, rectal, or breast exams. 
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
As clinically indicated, limited, symptom-directed physical examinations should be 
performed. Changes from baseline abnormalities should be recorded in the participant’s 
notes. New or worsened clinically significant abnormalities should be recorded as AEs 
on the Adverse Event eCRF. 
8.2.2 
Vital Signs 
Temperature, PR, and systolic and diastolic blood pressure will be assessed as outlined 
in the SoA (see Section 1.2). 
Blood pressure and pulse measurements will be assessed in a supine position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available. When possible, the same arm and device should be used for all 
blood pressure measurements. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell phones). 
8.2.3 
Electrocardiograms 
Single 12-lead ECGs will be obtained as outlined in the SoA (see Section 1.2) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. 


 
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To minimize variability, it is important that participants be in a resting position for 
≥10 minutes prior to each ECG evaluation. Supine 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. Electrocardiograms should be performed prior 
to any scheduled vital signs measurements and blood draws.  
8.2.4 
Clinical Safety Laboratory Assessments 
A list of clinical laboratory tests to be performed is provided in Appendix 4 and these 
assessments must be conducted in accordance with the SoA (Section 1.2). 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.  
• 
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. 
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified within participant’s 
standard of care and the Sponsor notified. 
 
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically-produced laboratory reports submitted directly from the local laboratory. 
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 and deemed clinically significant by 
the Investigator, or clinical symptoms necessitate additional testing to monitor participant 
safety. 
Where the clinical significance of abnormal laboratory results at Screening is considered 
uncertain, screening laboratory tests may be repeated to confirm eligibility once at 
Day -1. 
8.2.5 
Medical History and Demographic Data 
Medical history includes clinically significant diseases and all medications (e.g., 
prescription drugs, OTC drugs, herbal or homeopathic remedies, nutritional 
supplements) used by the participant within 30 days prior to the Screening visit. 
Demographic data will include age, sex, and self‑reported race/ethnicity. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The definitions of an AE or SAE can be found in Appendix 2. The non-serious AESIs 
(NSAESIs) are discussed in Section 8.3.6. 


 
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The Investigator and any qualified designees are responsible for ensuring that all AEs 
(including assessment of seriousness, severity, and causality; see Appendix 2) are 
recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Appendix 2. 
Procedures used for recording AEs are provided in Appendix 3: 
• 
Diagnosis versus signs and symptoms 
• 
AEs occurring secondary to other events 
• 
Persistent or recurrent AEs 
• 
Abnormal laboratory values 
• 
Abnormal vital signs values 
• 
Abnormal liver function tests 
• 
Deaths 
• 
Pre-existing medical conditions 
• 
Hospitalization or prolonged hospitalization. 
 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2 and 
Appendix 3 as applicable. 
Investigators will seek information on AEs at each participant’s contact. All AEs, whether 
reported by the participant or noted by study personnel, will be recorded in the 
participant’s medical record and on the Adverse Event eCRF as follows: 
After informed consent has been obtained but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention as judged by the Investigator 
should be reported. Any other AE should not be reported. 
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until the Follow-up visit. 
Post-study AEs and SAEs: The Investigator is not required to actively monitor 
participants for AEs after the end of the AE reporting period (after the Follow-up visit, 
defined as 10±2 days post final dose of study treatment; see SoA [Section 1.2]). 
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study treatment, at any 
time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study 


 
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participation, the Investigator must promptly notify the Sponsor. For the procedure of 
reporting, see Appendix 2. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all participant evaluation timepoints. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
8.3.3.1 
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 event is otherwise 
explained, the participant is lost to follow-up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered to be related to 
study treatment 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 participant’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 8.3.5. 
8.3.3.2 
Sponsor Follow-up 
For SAEs, NSAESIs, 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 summaries, consultant reports, 
autopsy reports) in order to perform an independent medical assessment of the reported 
case. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 


 
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investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and Investigators.  
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded 
to Investigators as necessary.  
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, Investigators, and IRB/EC, see Appendix 2. 
8.3.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours a day 7 days a week. Medical Monitor contact details will be available on a 
separate list generated by the study management team. 
8.3.5 
Pregnancy 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
90 days after the final dose of study drug. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5). 
8.3.6 
Non-serious Adverse Events of Special Interest 
Non-serious AESIs 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 Appendix 2 for 
reporting instructions). 
Non-serious AESIs for this study include the following: 
• 
Cases of an elevated ALT or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined in Appendix 3. 
• 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: 


 
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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 participant exposed to a medicinal product. This term applies only 
when a contamination of the study treatment is suspected. 
 
8.3.7 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
Not applicable for this healthy participant study. 
 
8.3.8 
Management of Specific Adverse Events 
Not applicable for this healthy participant study. 
8.4 
TREATMENT OF OVERDOSE 
Study treatment overdose is the accidental administration of a drug in a quantity that is 
higher than the assigned dose. An overdose or incorrect administration of study 
treatment is not an AE unless it results in untoward medical effects (see Section 5.2 of 
Appendix 2 for further details). 
Decisions regarding dose-interruptions or modifications (if applicable) will be made by 
the Investigator in consultation with the Medical Monitor based on the clinical evaluation 
of the participant. Such consultation should be adequately documented and archived in 
the site file. 
In the event of an overdose, the Investigator should: 
1. 
Contact the Sponsor’s Medical Monitor immediately. 
2. 
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved. 
3. 
Obtain a blood sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. 
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the eCRF (recorded in the comments of the AE or as additional observations). 
 
8.5 
PHARMACOKINETICS 
Mandatory blood samples to evaluate concentrations of study treatment (and its 
metabolite[s], if appropriate) will be collected. The date and time of each sample 
collection will be recorded in the eCRF. Risdiplam and midazolam (Part 2 only) levels 
will be analyzed by using validated assays. The PK samples will be taken as outlined in 
the Schedules of Activities tables (see Section 1.2). During the course of the study, PK 
sampling timepoints may be modified on the basis of emerging data to ensure the PK of 
study treatment can be adequately characterized. Metabolites may be measured by a 


 
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specific validated liquid chromatography with tandem mass spectrometry assay, or other 
fit for purpose methods as appropriate. 
The PK blood samples will be destroyed after the date of final Clinical Study Report or 
after approval of sample destruction by the study management team. Details on 
sampling procedures, sample storage, and shipment are given in the sample 
documentation. 
Any changes in the timing or addition of PK timepoints must be documented and 
approved by the relevant study team member and then archived in the Sponsor and site 
study files, but this will not constitute a protocol amendment.  
8.6 
IMMUNOGENICITY ASSESSMENTS 
Not applicable. 
8.7 
PHARMACODYNAMICS AND BIOMARKERS ANALYSES 
Not applicable; biomarkers are not evaluated in this study. 
8.8 
PHARMACODYNAMICS AND BIOMARKER SAMPLES 
Not applicable. 
8.9 
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY 
Not applicable. 
8.10 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION 
Health Economics/Medical Resource Utilization parameters are not evaluated in this 
study. 
8.11 
TIMING OF STUDY ASSESSMENTS 
8.11.1 
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 participants and for participants who are not subsequently enrolled will be 
maintained at the study site. 
All screening, and all pre-treatment assessments (related to entry criteria), must be 
completed and reviewed to confirm that participants meet all eligibility criteria. The 
Investigator will maintain a screening log to record details of all participants screened 
and to confirm eligibility or record reasons for screening failure. 
An Eligibility Screening Form documenting the Investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site. 


 
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Screening and pre-treatment assessments will be performed within 28 days prior to 
Day 1, unless otherwise specified.  
8.11.2 
Assessments During Treatment 
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified be permitted to re-enroll in the study. 
All assessments must be performed as per SoA (see Section 1.2). Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the SoA.  
8.11.3 
Assessments at Study Completion/Early Termination Visit 
Participants who complete the study or discontinue from the study early will be asked to 
return to the clinic 10±2 days after the final dose of study drug for a Follow-up visit.  
8.11.4 
Follow-up Assessments 
After the Study Completion/Early Termination visit, AEs should be followed as outlined in 
Sections 8.3.1 and 8.3.3. 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
SAMPLE SIZE DETERMINATION 
In total a maximum of 40 participants may be enrolled in this study as follows: 
• 
Part 1: 8 participants will be enrolled in order to obtain 6 evaluable participants. The 
Part 1 sample size was determined by practical considerations and not based on 
statistical power calculations. 
• 
Part 2: 28 participants will be enrolled in order to obtain at least 26 evaluable 
participants. The Part 2 sample size is based on estimates for the within-subject 
coefficient of variation of 26% and 35% for AUC extrapolated to infinity (AUCinf) and 
Cmax of midazolam, respectively, from a previous clinical study.13 A sample size of 
26 evaluable participants ensures that the two-sided 90% confidence interval for the 
geometric population mean of the individual exposure ratios of Day 16 to Day 1 will 
lie within the 0.75 to 1.33 limits of the geometric population mean with at least 80% 
probability (power). 
The additional 4 participants are in case the dropout rate in Part 2 is higher than 
expected in order to achieve 26 evaluable participants. 


 
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9.2 
POPULATIONS FOR ANALYSES 
For purposes of analysis, the following populations are defined in Table 4. 
Table 4 
Analysis Populations 
Population 
Description 
Safety 
All participants who received at least 1 dose of the study 
treatment, whether prematurely withdrawn from the study or 
not, will be included in the safety analysis.  
Pharmacokinetic 
All participants who have received at least 1 dose of study 
treatment and who have data from at least 1 postdose PK 
sample will be included in the PK analysis population. 
Participants will be excluded from the PK analysis population if 
they significantly violate the inclusion or exclusion criteria, 
deviate significantly from the protocol, or if data are 
unavailable or incomplete which may influence the PK 
analysis. Excluded cases will be documented together with the 
reason for exclusion. All decisions on exclusions from the 
analysis will be made prior to database closure. 
 
9.3 
STATISTICAL ANALYSES 
9.3.1 
Safety Analyses 
All safety analyses will be based on the safety analysis population. Safety analyses are 
detailed in Table 5. 
No formal statistical analyses of the safety data are planned. 
Table 5 
Safety Statistical Analysis Methods 
Endpoint 
Statistical Analysis Methods 
Adverse events 
The original terms recorded on the eCRF by the Investigator for adverse 
events will be coded by the Sponsor. 
Adverse events will be summarized by mapped term and appropriate 
thesaurus level. 
Clinical laboratory 
tests 
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Laboratory test values will be presented in 
International System of Units (SI units; Système International d’Unités) by 
individual listings with flagging of abnormal results. Summaries of clinical 
laboratory tests will also be used, as appropriate. 
Vital signs 
Vital signs data will be presented by individual listings with flagging of 
values outside the normal ranges and flagging of abnormalities. In addition, 
tabular summaries will be used, as appropriate. 
ECG data analysis ECG data will be presented by individual listings. In addition, tabular 
summaries will be used, as appropriate. 


 
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Concomitant 
medications 
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by utilizing 
a mapped term and appropriate drug dictionary level. 
Concomitant medications will be presented in summary tables and listings. 
 
9.3.2 
Pharmacokinetic Analyses 
Analyses will be carried out on the PK analysis population. All PK parameters will be 
presented by listings and descriptive summary statistics (arithmetic mean, standard 
deviation, geometric mean, geometric coefficient of variation, median, minimum, and 
maximum). For Tmax, only the median, minimum, and maximum values will be presented. 
Pharmacokinetic parameters will be read directly from the plasma concentration-time 
profiles, or calculated using standard non-compartmental methods.  
The following PK parameters will be computed for risdiplam and its metabolite(s) as 
appropriate and midazolam and its metabolite(s) as appropriate. Other PK parameters 
might be computed in addition as appropriate. 
• 
Tmax  
Time of maximum observed plasma concentration 
• 
Cmax  
Maximum observed plasma concentration 
• 
Ctrough 
Trough observed plasma concentration 
• 
AUCtau 
Area under the plasma concentration-time curve over a dosing interval 
• 
AUClast 
Area under the plasma concentration-time curve from time 0 to the 
  
 
time of last quantifiable concentration (tlast) 
• 
AUCinf 
Area under the plasma concentration-time curve extrapolated to infinity 
• 
λz 
 
Apparent terminal elimination rate constant 
• 
t½ 
 
Apparent plasma terminal elimination half-life 
• 
CLss/F 
Apparent total plasma clearance at steady state 
• 
ARAUC 
Accumulation ratio for AUC 
• 
ARCmax 
Accumulation ratio for Cmax 
No formal statistical analyses are planned for Part 1. 
In Part 2, the effect of multiple oral doses of risdiplam on the PK of a single oral dose of 
midazolam (and its metabolite[s] as appropriate) will be explored using an analysis of 
variance applied to the log-transformed PK parameters Cmax and AUCinf (or, if AUCinf 


 
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cannot be properly estimated, AUClast or an alternate partial AUC from time zero to a 
common postdose time, AUC0-t). The model will include treatment as a fixed effect and 
subject as a random effect. From the model estimates, the geometric mean ratios 
(midazolam alone versus midazolam in combination with risdiplam) will be derived 
together with corresponding two-sided 90% confidence intervals.  
9.4 
INTERIM ANALYSES 
No formal interim analysis is planned. Data from Part 1 will be evaluated before the start 
of Part 2, and the dose selection for Part 2 will be based on Part 1 data. 
9.5 
SUMMARIES OF CONDUCT OF STUDY 
All protocol deviations will be listed. Data for study drug administration and concomitant 
medication will be listed. The number of participants who were enrolled, discontinued, 
and completed the study will be summarized and listed. 
10. 
REFERENCES 
1. RO7034067 – Investigator’s Brochure (Version 6). March 2019.  
2. Crawford TO, Pardo CA. The neurobiology of childhood spinal muscular atrophy. 
Neurobiol Dis. 1996 Apr;3(2):97–110.  
3. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008 Jun 
21;371(9630):2120–33.  
4. Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, et al. Pan-ethnic 
carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical 
laboratory analysis of >72,400 specimens. Eur J Hum Genet EJHG. 2012 
Jan;20(1):27–32.  
5. Lorson CL, Rindt H, Shababi M. Spinal muscular atrophy: mechanisms and 
therapeutic strategies. Hum Mol Genet. 2010 Apr 15;19(R1):R111-8.  
6. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. 
Identification and characterization of a spinal muscular atrophy-determining gene. 
Cell. 1995 Jan 13;80(1):155–65.  
7. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene 
regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci 
USA. 1999 May 25;96(11):6307–11.  
8. Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011 
Aug;68(8):979–84.  
9. Nurputra DK, Lai PS, Harahap NIF, Morikawa S, Yamamoto T, Nishimura N, et al. 
Spinal muscular atrophy: from gene discovery to clinical trials. Ann Hum Genet. 2013 
Sep;77(5):435–63.  


 
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10. European Medicines Agency (EMA). Guideline on the Investigation of Drug 
Interactions. CPMP/EWP/560/95/Rev. 1 Corr. 2. 21 June 2012. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/0
7/WC500129606.pdf. 
11. Midazolam. In: DRUGDEX System (Micromedex 2.0). Greenwood Village, CO: 
Truven Health Analytics; c1974-2013. Available from: 
http://www.micromedexsolutions.com/micromedex2/librarian#. 
12. Hohmann N,  Kocheise F, Carls A, Burhenne J, Haefeli WE, Mikus G. Midazolam 
microdose to determine systemic and pre-systemic metabolic CYP3A activity in 
humans. Br J Clin Pharmacol. 2014 Feb. 79(2):278–85. 
13. 
, et al. The bioavailability and pharmacodynamics of 
midazolam (RO 21-3981 and its 1’-hydroxymethyl midazolam metabolite (RO 21-
6347) following single dose intravenous, intramuscular, oral solution, and oral tablet 
administration to normal subjects. Research Report N-36884, October 9, 1982. 
 


 
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Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations 
1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
1.1. 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the International Conference for 
Harmonisation (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 (US) or under a US Investigational New Drug (IND) application will 
comply with US Food and Drug Administration regulations and applicable local, state, 
and federal laws. Studies conducted in the European Union/European Economic Area 
will comply with the EU Clinical Trial Directive (2001/20/EC). 
1.2. 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms (ICFs), any information to be given to the 
participant (e.g., advertisements, diaries etc), and relevant supporting information must 
be submitted to the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) by the Principal Investigator and reviewed and approved by the IRB/IEC before the 
study is initiated. In addition, any participant recruitment materials must be approved by 
the IRB/IEC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/IEC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/IEC. Investigators are 
also responsible for promptly informing the IRB/IEC of any protocol amendments 
(Section 2.3.1 of this Appendix). 
The Investigator should follow the requirements for reporting all adverse events (AEs) to 
the Sponsor. 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/IEC, and archived in the site’s 
study file. 
1.3. 
INFORMED CONSENT 
The Sponsor’s Master ICF (and ancillary sample ICFs such as a Child’s Assent or 
Caregiver's ICF, if applicable) will be provided to each site. If applicable, it will be 
provided in a certified translation of the local language. Participants must be informed 
that their participation is voluntary. Participants will be required to sign a statement of 
informed consent that meets the requirements of 21 Code of federal Regulations 50, 


 
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local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. The Sponsor 
or its designee must review and approve any proposed deviations from the Sponsor's 
sample ICFs or any alternate consent forms proposed by the site (collectively, the 
“Consent Forms”) before IRB/IEC submission. The final IRB/IEC-approved Consent 
Forms must be provided to the Sponsor for Health Authority submission purposes 
according to local requirements. Participants must be re-consented to the most current 
version of the ICF(s) during their participation in the study. A copy of the ICF(s) signed 
by all parties must be provided to the participant or the participant’s legally authorized 
representative. 
The Consent Forms must be signed and dated by the participant or the participant’s 
legally authorized representative before his or her participation in the study. The case 
history or clinical records for each participant shall document the informed consent 
process and that written informed consent was obtained prior to participation in the 
study. 
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 
participant to take part. The final revised IRB/IEC-approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes if required as per local 
regulations. 
Participants 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/IEC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each participant 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 participant or the 
participant’s legally authorized representative. All signed and dated Consent Forms must 
remain in each participant’s study file or in the site file and must be available for 
verification by study monitors at any time. 
1.4. 
CONFIDENTIALITY 
Participants will be assigned a unique identifier by the Investigator. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable will 
not be transferred.  
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant.  


 
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Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes. 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study. These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request. 
1.5. 
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 1 year after completion of the study (i.e., last participant last 
visit [LPLV]). 
2. 
DATA HANDLING AND RECORD 
2.1. 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
2.1.1. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic Case 
Report Form (CRF) unless transmitted to the Sponsor or designee electronically (e.g., 
laboratory data). The Investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 


 
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Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH Good Clinical Practice (GCP), and all applicable regulatory 
requirements. 
2.1.2. 
Source Data Records 
Source documents (paper or electronic) are those in which participant 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, 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 electronic CRFs (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 electronic CRFs must not be obliterated or destroyed and must be 
retained per the policy for retention of records described below. 
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/IEC review. The investigational site must also allow 
inspection by applicable Health Authorities. 
2.1.3. 
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. 
2.2. 
RETENTION OF RECORDS 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records 


 
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may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
2.3. 
STUDY RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/IEC and governmental approval.  
Roche shall also submit an Annual Safety Report once a year to the IRB/IEC according 
to local regulatory requirements and timelines of each country participating in the study. 
2.3.1. 
Protocol Amendments 
Any substantial protocol amendments will be prepared by the Sponsor or authorized 
designee. Substantial protocol amendments will be submitted to the IRB/IEC and to 
regulatory authorities in accordance with local regulatory requirements. 
Approval must be obtained from the IRB/IEC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or any non-substantial changes, as 
defined by regulatory requirements. 
2.3.2. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. 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 will be designated by mutual agreement. 
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. 


 
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2.3.3. 
Site Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ medical records, and electronic CRFs. The 
Investigator will permit national and local Health Authorities, Sponsor monitors, 
representatives, and collaborators, and the IRBs/IECs to inspect facilities and records 
relevant to this study. 
3. 
ADMINISTRATIVE STRUCTURE 
The Sponsor of the trial is F. Hoffmann-La Roche Ltd. 
Covance is the contract research organization. 
4. 
STUDY AND SITE CLOSURE 
The Sponsor (or designee) has the right to close the study site or 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 participants. 
• 
Participant enrollment is unsatisfactory. 
 
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. 
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study site closure 
visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines. 
• 
Inadequate recruitment of participants by the Investigator. 
• 
Discontinuation of further study treatment development. 
 


 
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Appendix 2  
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up, and Reporting 
1. 
DEFINITION OF ADVERSE EVENTS 
According to the E2A International Conference for Harmonisation guideline for Good 
Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be: 
• 
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. 
 
Events Meeting the AE Definition: 
• 
Deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) or 
other clinical test (e.g., electrocardiogram, X-ray) that is associated with symptoms 
or leads to a change in study treatment or concomitant treatment or discontinuation 
from study treatment (see Appendix 3, Section 4). 
• 
Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Adverse events 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). 
 
Events NOT Meeting the AE Definition: 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 


 
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2. 
DEFINITION OF SERIOUS ADVERSE EVENTS 
If an event is not an AE per definition above, then it cannot be a serious AE (SAE) even 
if serious conditions are met (e.g., hospitalization for signs/symptoms of the disease 
under study, death due to progression of disease). 
An SAE is defined as any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening. 
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(see Appendix 3). 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity 
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect. 
• 
Other significant events: 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
1 of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 


 
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convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
3. 
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
The Investigator will then record all relevant AE/SAE information in the Case Report 
Form (CRF). 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the electronic CRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
3.1. 
ASSESSMENT OF SEVERITY 
The Investigator will make an assessment of severity for each AE and SAE reported 
during the study and assign it to 1 of the categories provided in Table 1 below (as a 
guidance for assessing AE severity). 
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 
[e.g., National Cancer Institute Common Terminology Criteria for Adverse Events 
criteria]); 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 electronic CRF. 
Serious AEs are required to be reported by the Investigator to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event). 


 
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Table 1 
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 above). 
 
3.2. 
ASSESSMENT OF CAUSALITY 
Investigators should use their knowledge of the participant, 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 treatment, 
indicating "yes" or "no" accordingly. The following guidance should be taken into 
consideration: 
• 
Temporal relationship of event onset to the initiation of study treatment. 
• 
Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment (where 
applicable). 
• 
Known association of the event with the study treatment or with similar treatments. 
• 
Known association of the event with the disease under study. 
• 
Presence of risk factors in the participant 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 participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
4. 
FOLLOW-UP OF AES AND SAES 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
New or updated information will be recorded in the originally completed CRF. 


 
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The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
5. 
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 treatment: 
• 
Serious AEs. 
• 
Non-serious adverse events of special interest (NSAESI). 
• 
Pregnancies (see Section 8.3.5). 
 
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 Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC). 
5.1 
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST 
Events That Occur Prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
SAEs caused by a protocol-mandated intervention should be reported. The Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form provided to 
Investigators should be completed and submitted to the Serious Adverse Event 
Responsible person immediately (i.e., no more than 24 hours after learning of the event). 


 
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Events That Occur After Study Treatment Initiation 
For reports of SAEs and NSAESIs (Section 8.3.6) that occur after initiation of study 
treatment (Section 8.3.1), Investigators should record all case details that can be 
gathered immediately (i.e., within 24 hours after learning of the event) on the paper 
Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
and submit to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to Investigators. 
Reporting of Post-Study Adverse Events and Serious Adverse Events 
If the Investigator becomes aware of any other SAEs occurring after the end of the AE 
reporting period, if the event is believed to be related to prior study treatment, the event 
should be reported directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the SAE Reporting Form using the fax number or email address 
provided to Investigators. 
5.2 
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR (SPECIAL SITUATIONS) 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations") are defined as follows: 
• 
Accidental overdose: accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error: accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Special situations are not in themselves AEs, but may result in AEs. Each AE associated 
with a special situation should be recorded separately on the Adverse Event electronic 
CRF. If the associated AE fulfills seriousness criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event). For 
risdiplam, AEs associated with special situations should be recorded as described below 
for each situation: 
• 
Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
• 
Medication error that does not qualify as an overdose: Enter the AE term. Check the 
"Medication error" box. 
• 
Medication error that qualifies as an overdose: Enter the AE term. Check the 
"Accidental overdose" and "Medication error" boxes.  
 


 
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In addition, all special situations associated with risdiplam, regardless of whether they 
result in an AE, should be recorded on the Adverse Event electronic CRF. Special 
situations should be recorded as described below: 
• 
Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
• 
Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details. 
• 
Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require the 
completion of 2 Adverse Event electronic CRF pages, 1 to report the accidental 
overdose and 1 to report the headache. The "Accidental overdose" and "Medication 
error" boxes would need to be checked on both electronic CRF pages. 
6. 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and NSAESI against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
Investigators, IRBs, IECs, 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 following reference documents: 
• 
Risdiplam 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. 


 
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Appendix 3  
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events (AEs) on the Adverse Event electronic Case Report Form (eCRF). Avoid 
colloquialisms and abbreviations. 
Only 1 AE term should be recorded in the event field on the Adverse Event eCRF. 
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 
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 1 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. 
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 3 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. 
3. 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between participant 
evaluation timepoints. Such events should only be recorded once on the Adverse Event 


 
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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 participant evaluation timepoints and 
subsequently recurs. Each recurrence of an AE should be recorded separately on the 
Adverse Event eCRF. 
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). 
• 
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., alkaline phosphatase and bilirubin 5 times the upper limit of normal [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. 


 
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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 signs 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 blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
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. 
6. 
ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated alanine aminotransferase (ALT) or aspartate 
aminotransferase (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. 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. 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (Section 8.2.4 and 
Appendix 2) and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event), either as an SAE or a NSAESI (Appendix 2). 
7. 
DEATHS 
All deaths that occur during the protocol-specified AE reporting period (see Section 5 of 
Appendix 2), regardless of relationship to study treatment, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor.  


 
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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 1 such event should be reported. 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. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
8. 
PRE-EXISTING MEDICAL CONDITIONS 
A pre-existing 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 pre-existing 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 
pre-existing condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
9. 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE (per the definition of SAE in Appendix 2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an AE or an SAE: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration) 
• 
Hospitalization for a pre-existing condition, provided that all of the following criteria 
are met: 
o The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of the 
expected normal progression of the disease. 
o The participant has not suffered an AE. 
An event that leads to hospitalization under the following circumstances is not 
considered to be an SAE, but should be reported as an AE instead: 
• 
Hospitalization for an AE that would ordinarily have been treated in an outpatient 
setting had an outpatient clinic been available. 


 
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Appendix 4  
Clinical Laboratory Tests 
The tests detailed in Table 1 will be performed by the local laboratory in Parts 1 and 2. If 
the local laboratory results are used, the results must be captured in source 
documentation and entered into the electronic Case Report Form (CRF). 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 1 
Protocol-Required Safety Laboratory Assessments 
Serum biochemistry: 
Urinalysis: 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase 
Gamma-glutamyl transferase (GGT) 
Sodium 
Potassium 
Chloride 
Calcium 
Inorganic phosphate 
Glucose 
Urea 
Bilirubin (Total and Direct) 
Creatinine 
Total protein 
Albumin 
Cholesterol 
Triglycerides 
Thyroid-stimulating hormone (TSH) c 
Microscopic examination (sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, 
bacteria), if blood or protein is abnormal. 
pH 
Protein 
Glucose 
Blood 
 
Urinary drug screen: 
Drugs of abuse a 
 
Hormone panel: b, c 
Follicle-stimulating hormone (FSH) d 
Estradiol d 
Human chorionic gonadotropin (hCG) (serum 
pregnancy test) 
 
Serology: c 
Hepatitis B surface antigen (HBsAg) 
Hepatitis C antibody 
Human immunodeficiency virus (HIV) 
antibodies 
 
Coagulation: c 
International normalized ratio (INR) 
Activated partial thromboplastin time (aPTT) 
Prothrombin time (PT) 
Hematology: 
White blood cell count (WBC) 
Red blood cell count (RBC) 
Hemoglobin 
Hematocrit 
Platelet count 
Differential WBC (basophils, neutrophils, 
eosinophils, monocytes, and lymphocytes) 
a Opiates, amphetamines, cannabinoids, benzodiazepines, cocaine, barbiturates, methadone, 
cotinine, and alcohol. 
b Females only. 
c Analyzed at Screening only. 
d Post-menopausal females only. 
 
The results of each test must be entered into the CRF. 
Investigators must document their review of each laboratory safety report. 


 
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Additional Statistical Considerations for Clinical Laboratory Data 
• 
Standard Reference Ranges and Transformation of Data 
Potential analysis considerations for analyzing laboratory data includes the use of 
standard reference ranges and potential transformation of data for specific lab tests.  
In this scenario, Roche standard reference ranges, rather than the reference ranges of 
the Investigator, can be used for specific parameters. For these 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 aspartate aminotransferase, alanine aminotransferase, and alkaline 
phosphatase 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. 
• 
Definition of Laboratory Abnormalities 
For all laboratory parameters included in this analysis, there exists a Roche predefined 
standard reference range. Laboratory values falling outside this standard reference 
range will be labeled “H” for high or “L” for low in participant listings of laboratory data. 
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for these laboratory parameters. 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 participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low. 
 


 
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Appendix 5  
Contraceptive Guidance and Collection of Pregnancy 
Information 
1. 
DEFINITIONS 
• 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements. 
• 
Women in the following categories are considered to be a Woman of 
Non-Childbearing Potential (WONCBP) 
a) 
Pre-menarchal 
b) 
Pre-menopausal female with 1 of the following: 
– 
Documented hysterectomy. 
– 
Documented bilateral salpingectomy. 
– 
Documented tubal ligation. 
– 
Documented bilateral oophorectomy. 
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
c) 
Post-menopausal female 
– 
A post-menopausal state is defined as no menses for ≥ 12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient. 
– 
Females on HRT and whose menopausal status is in doubt will be required to use 
1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment. 
 


 
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2. 
CONTRACEPTION GUIDANCE 
• 
Female Participants 
Not applicable; female participants of childbearing potential (WOCBP) will not be allowed 
to participate in this study. Women of non-childbearing potential are eligible for the 
study. Both are defined in Section 1 above. 
• 
Male Participants 
Use of adequate contraception methods during the treatment period and until 4 months 
after last study drug administration. Males must refrain from donating sperm during this 
same period.  
a) Contraception methods for male participants considered as acceptable for the study:  
o With non-pregnant female partners, use contraceptive measures such as a 
condom with spermicide plus an additional contraceptive method that together 
result in a failure rate of <1% per year, with partners who are WOCBP (as 
defined in Section 1 above). The additional contraceptive method must be 1 of 
the following: diaphragm in combination with spermicide, intrauterine device, 
injectable or implantable contraceptives, oral hormonal contraceptives (e.g., 
“progesterone only pills,” tablets, patch, or vaginal ring with both estrogen and 
progesterone). Contraception is required during the treatment period and for 
at least 4 months after the last dose of risdiplam. 
o With pregnant female partners, use contraceptive measures such as a 
condom to avoid exposing the embryo during the treatment period and for at 
least 28 days after the last dose of risdiplam. 
Abstinence (including those who practice abstinence as part of their normal and 
preferred lifestyle, periodic abstinence, e.g., calendar, ovulation, symptothermal, or 
post ovulation methods) and withdrawal are not acceptable methods of 
contraception in this study. 
3. 
PREGNANCY TESTING 
Female participants of childbearing potential will not be allowed to participate in this 
study. Blood sample and urine pregnancy tests will be performed according to Schedule 
of Activity tables (see Section 1.2). If a urine pregnancy test is positive, it must be 
confirmed by a blood pregnancy test. 
4. 
COLLECTION OF PREGNANCY INFORMATION 
• 
Male participants with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5 Pregnancy). 


 
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Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The 
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. If the authorization has been signed, the Investigator should update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant 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. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
5 
ABORTIONS 
Any spontaneous abortion should be classified as an SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the Adverse 
Event electronic Case Report Form (eCRF), and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5 of Appendix 2). 
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as an SAE, 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 of Appendix 2). 
Elective or therapeutic abortion not associated with an underlying maternal or 
embryo-fetal toxicity (e.g., induced abortion for personal reasons) does not require 
expedited reporting but should be reported as outcome of pregnancy on the Clinical Trial 
Pregnancy Reporting Form. 
6 
CONGENITAL ANOMALIES/BIRTH DEFECTS 
Any congenital anomaly/birth defect in a child born to a female partner of a male 
participant exposed to study treatment should be classified as an SAE, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event). 
 

SAP_001.pdf: 
 
Official Title: 
 
A Phase I, 2-Part, Open-Label Study to Investigate the Safety, 
Tolerability, and Pharmacokinetics of Multiple Doses of Risdiplam 
and the Effect of Risdiplam on the Pharmacokinetics of Midazolam 
Following Oral Administration in Healthy Participants  
NCT Number: 
NCT03988907  
Document Date: 
SAP Version 1: 07-October-2019 
 
 
 


Version 1, Final 1: 2 October 2019 
 
Page 1 of 19 
 
STATISTICAL ANALYSIS PLAN 
A PHASE I, 2-PART, OPEN-LABEL STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF MULTIPLE DOSES OF 
RISDIPLAM AND THE EFFECT OF RISDIPLAM ON THE PHARMACOKINETICS 
OF MIDAZOLAM FOLLOWING ORAL ADMINISTRATION IN HEALTHY 
PARTICIPANTS 
Statistical Analysis Plan Version: 1 
Statistical Analysis Plan Status: Final 1 
Statistical Analysis Plan Date: 2 October 2019 
Study Drug: Risdiplam (RO7034067) 
Sponsor Reference Number: BP41361 
Covance Study Number: 8406533 
Clinical Phase 1 
 
 
Sponsor: 
F. Hoffmann-La Roche Ltd. 
Grenzacherstrasse 124 
4070 Basel 
Switzerland 
Study Sites: 
Covance Dallas Clinical Research Unit 
1341 W. Mockingbird Lane 
Suite 200E 
Dallas 
TX 75247 
USA 
 
 
Sponsor Signatory: 
, MSc 
Statistician 
Principal Investigator: 
Dr 
, MD 
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Page 3 of 19 
 
2  TABLE OF CONTENTS 
1 
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ................................... 2 
2 
TABLE OF CONTENTS ................................................................................................... 3 
3 
ABBREVIATIONS ............................................................................................................ 4 
4 
INTRODUCTION .............................................................................................................. 6 
5 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 6 
6 
STUDY DESIGN ............................................................................................................... 7 
7 
TREATMENT .................................................................................................................... 8 
8 
SAMPLE SIZE JUSTIFICATION ..................................................................................... 9 
9 
DEFINITION OF ANALYSIS POPULATIONS .............................................................. 9 
10 STATISTICAL METHODOLOGY ................................................................................... 9 
10.1 General ......................................................................................................................... 9 
10.1.1 Definition of Baseline and Change from Baseline ........................................... 10 
10.1.2 Repeat and Unscheduled Readings .................................................................. 10 
10.2 Demographics, Baseline Characteristics and Subject Disposition ............................ 11 
10.3 Pharmacokinetic Assessment ..................................................................................... 11 
10.3.1 Pharmacokinetic Analysis ................................................................................ 11 
10.3.2 Presentation of Pharmacokinetic Data ............................................................. 15 
10.3.3 Pharmacokinetic Statistical Methodology ........................................................ 15 
10.4 Safety and Tolerability Assessments ......................................................................... 16 
10.4.1 Adverse Events ................................................................................................. 16 
10.4.2 Clinical Laboratory Parameters ........................................................................ 16 
10.4.3 Vital Signs ........................................................................................................ 17 
10.4.4 Electrocardiogram ............................................................................................ 17 
10.4.5 Previous and Concomitant Medications ........................................................... 18 
10.4.6 Other Assessments ........................................................................................... 18 
10.4.7 Safety and Tolerability Statistical Methodology .............................................. 18 
11 INTERIM ANALYSES .................................................................................................... 18 
12 CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ....... 19 
13 DATA PRESENTATION ................................................................................................ 19 
13.1 Insufficient Data for Presentation ............................................................................... 19 
14 REFERENCES ................................................................................................................. 19 
 
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3  ABBREVIATIONS 
Abbreviations pertain to the SAP only (not the TFLs). 
z 
apparent terminal elimination rate constant 
ADaM 
analysis data model 
AE 
adverse event(s) 
ARAUC 
accumulation ratio for AUC 
ARCmax 
accumulation ratio for Cmax  
AUC 
area under the plasma concentration-time curve 
AUCinf 
area under the concentration-time curve from time zero extrapolated to infinity 
AUClast 
area under the plasma concentration-time curve from time zero to the time of 
last quantifiable concentration (tlast) 
AUCtau 
area under the plasma concentration-time curve from time zero to the end of the 
dosing interval 
BLQ 
below the limit of quantification  
BMI 
body mass index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence intervals  
CL/F 
apparent total plasma clearance after oral administration 
CLss/F 
apparent total plasma clearance at steady state 
Clast 
observed plasma concentration at time of last quantifiable plasma concentration 
Cmax 
maximum observed plasma concentration 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
Ctrough 
trough observed plasma concentration 
CV% 
coefficient of variation 
ECG 
electrocardiogram 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRAUC 
metabolite:parent ratio of AUC 
MRCmax 
metabolite:parent ratio of Cmax 
MW 
molecular weight 
NC 
not calculated 
NR 
no result 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTcF 
QTc calculated using the Fridericia’s correction 
R2-adjusted 
adjusted coefficient of determination for exponential fit 
SAE 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SMA 
spinal muscular atrophy 
t1/2 
apparent plasma terminal elimination half-life 
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TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tlast 
time of last quantifiable plasma concentration 
Tmax 
time of the maximum observed plasma concentration 
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4  INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1 dated 
23 April 2019). 
This SAP describes the planned analysis of the safety, tolerability, and PK data from this study. 
A detailed description of the planned TFLs to be presented in the Clinical Study Report (CSR) is 
provided in the accompanying TFL shell document. 
The intent of this document is to provide guidance for the statistical analyses of PK and safety 
data. In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement between F. Hoffmann La Roche Ltd. and Covance. A limited amount of 
information concerning this study (eg, objectives, study design) is given to help the reader’s 
interpretation. This SAP must be finalised prior to the lock of the clinical database for this study. 
When the SAP and TFL shells are agreed upon and finalized, they will serve as the template for 
this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between F. Hoffmann La Roche Ltd. and Covance and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline entitled, “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH E3 guideline entitled, “Guidance for Industry: 
Structure and Content of Clinical Study Reports.”1,2 
5  STUDY OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints are provided in Table 1. 
Table 1: Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To investigate the effect of multiple oral doses of 
risdiplam on the PK of a single oral dose of midazolam 
in healthy participants. 
Midazolam concentrations and thereof derived PK 
parameters for midazolam (and its metabolite[s] as 
appropriate) alone and in combination with risdiplam. 
 
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Objectives 
Endpoints 
Secondary 
 
To assess the safety and tolerability of a single oral dose 
of midazolam alone and in combination with multiple 
oral doses of risdiplam in healthy participants. 
Incidence and severity of adverse events (AEs); changes 
in vital signs, physical findings, electrocardiogram 
(ECG) parameters, and clinical laboratory test results 
during and after midazolam administration alone and in 
combination with risdiplam. 
To assess the safety and tolerability of multiple oral 
doses of risdiplam administered once daily (QD) for 
14 days. 
Incidence and severity of AEs; changes in vital signs, 
physical findings, ECG parameters, and clinical 
laboratory test results during and after administration of 
multiple doses of risdiplam. 
To assess the PK of risdiplam (and its metabolite[s] as 
appropriate) following multiple oral doses of risdiplam 
QD for 14 days. 
Concentrations and thereof derived PK parameters for 
risdiplam and its metabolite(s) as appropriate. 
 
6  STUDY DESIGN 
This will be a Phase I, 2-part, open-label, non-randomized study to investigate the safety, 
tolerability, and PK of a multiple-dosing regimen of risdiplam (QD; Part 1) and the effect of 
risdiplam on the PK of midazolam (Part 2) following oral administration in healthy adult male 
and female participants. 
In total a maximum of 40 participants may be enrolled in this study as follows: 
 Part 1: 8 participants will be enrolled in order to obtain at least 6 evaluable participants. 
 Part 2: 28 participants will be enrolled in order to obtain at least 26 evaluable participants. 
The additional 4 participants are in case the dropout rate is higher than expected in order to 
achieve a sufficient number of evaluable participants. Participants enrolled in Part 1 of this study 
must not be enrolled in Part 2. 
In Part 1, participants will receive a dose of 5 mg risdiplam QD for 14 consecutive days. The 
dose of 5 mg risdiplam has been shown to be safe and well tolerated for more than 1 year of 
treatment in patients with spinal muscular atrophy (SMA). The decision to proceed to Part 2 of 
the study will be made following review of all available safety and tolerability data, including 
AEs, ECGs, vital signs, laboratory safety test results (i.e., hematology, clinical chemistry, and 
urinalysis) collected up to (and including) 48 hours after last study drug administration and 
available plasma PK data up to (and including) 24 hours after last study drug administration from 
a minimum of 4 Part 1 participants. The risdiplam dose in Part 2 will be determined based on the 
PK and safety data obtained in Part 1, with the aim to achieve an average exposure (mean 
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concentration-time curve [AUC] over a dosing interval [AUCtau] at steady state) of 
2000 ng.h/mL in Part 2 (i.e., the therapeutic exposure observed in SMA patients). 
A Dose Escalation Meeting will be conducted prior to the start of Part 2, in order to evaluate the 
Part 1 data and to select the risdiplam dose to be administered in Part 2 of this study. 
In Part 2, all study participants will receive a single oral dose of 2 mg midazolam on Day 1. On 
Day 3, the 14-day QD treatment period with risdiplam will begin (targeting a mean AUCtau at 
steady state of 2000 ng.h/mL; the precise dose will be based on the results of Part 1), with single 
dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of 
risdiplam). 
7  TREATMENT 
Part 1 
The following is the treatment naming convention that will be used in all TFLs: 
Treatment 
5 mg risdiplam QD 
Part 2 
The following is the treatment naming convention and ordering that will be used in all TFLs for 
PK and AE data. 
Treatment 
Order in TFLs 
2 mg midazolam 
1 
8 mg risdiplam QD 
2 
2 mg midazolam and 8 mg risdiplam QD 
3 
The following is the treatment sequence naming convention that will be used in all other TFLs. 
Treatment Sequence 
Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg 
risdiplam QD; Day 16: 8 mg risdiplam QD 
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8  SAMPLE SIZE JUSTIFICATION 
In total a maximum of 40 participants may be enrolled in this study as follows: 
 Part 1: 8 participants will be enrolled in order to obtain 6 evaluable participants. The Part 1 
sample size was determined by practical considerations and not based on statistical power 
calculations. 
 Part 2: 28 participants will be enrolled in order to obtain at least 26 evaluable participants. 
The Part 2 sample size is based on estimates for the within-subject coefficient of variation of 
26% and 35% for AUC extrapolated to infinity (AUCinf) and Cmax of midazolam, respectively, 
from a previous clinical study3. A sample size of 26 evaluable participants ensures that the 
two-sided 90% confidence interval for the geometric population mean of the individual 
exposure ratios of Day 16 to Day 1 will lie within the 0.75 to 1.33 limits of the geometric 
population mean with at least 80% probability (power). 
The additional 4 participants are in case the dropout rate in is higher than expected. 
9  DEFINITION OF ANALYSIS POPULATIONS 
Safety Population: all participants who received at least 1 dose of the study treatment (risdiplam 
or midazolam), whether prematurely withdrawn from the study or not, will be included in the 
safety analysis. 
PK Population: all participants who have received at least 1 dose of study treatment (risdiplam 
or midazolam), and who have data from at least 1 postdose PK sample will be included in the PK 
analysis population. Participants will be excluded from the PK analysis population if they 
significantly violate the inclusion or exclusion criteria, deviate significantly from the protocol, or 
if data are unavailable or incomplete which may influence the PK analysis. Excluded cases will 
be documented together with the reason for exclusion. All decisions on exclusions from the 
analysis will be made prior to database closure. 
All Subjects Population: any participants who signed informed consent. 
All protocol deviations that occur during the study will be considered prior to database lock for 
their severity/impact and will be taken into consideration when subjects are assigned to analysis 
populations. Protocol deviations will be listed. Details of subject assignment to the analysis 
populations will be listed. 
10  
STATISTICAL METHODOLOGY 
10.1 General 
Data listings will be provided for the All Subjects Population. Summary statistics and statistical 
analyses will be performed for subjects included in the relevant analysis populations 
(Safety/PK). Data will be summarized separately by part. 
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For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation, median, minimum, maximum, and number. For log-normal data (eg, the PK 
parameters: area under the plasma concentration-time curve [AUC] and maximum observed 
plasma concentration [Cmax]), the geometric mean and geometric coefficient of variation (CV%) 
will also be presented. For categorical data, frequency counts and percentages will be presented. 
Data listings will be provided for all subjects up to the point of withdrawal, with any subjects 
excluded from the relevant population highlighted. For the calculation of summary statistics and 
statistical analysis, unrounded data will be used. 
Missing values will not be imputed. 
Data analysis will be performed using SAS® Version 9.4 or higher. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1, and CDISC ADaM Implementation Guide 
Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilised to ensure 
compliance with CDISC standards. 
10.1.1 Definition of Baseline and Change from Baseline 
Baseline for each parameter is defined as the last value measured prior to dosing, including 
repeat (vital signs and ECGs) and unscheduled (clinical laboratory parameters) readings (see 
Section 10.1.2 for definitions of repeat and unscheduled readings). 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. 
10.1.2 Repeat and Unscheduled Readings 
Repeat readings occur when the original vital signs or ECG result requires confirmation. Repeat 
readings are labelled as ‘Repeat’ in the listings and replace the original readings in all summaries 
and changes from baseline presentations and calculations. Prior to dosing, all readings taken in 
addition to the original reading are defined as predose repeats. Postdose repeat readings are 
defined as readings collected within 15 minutes of the actual time of the original reading. Where 
results are taken in triplicate and repeated, the last 3 readings are used in all subsequent 
calculations. 
With the exception of predose results described above, unscheduled readings for vital signs or 
ECGs are defined as readings collected >15 minutes from the actual time of the original reading. 
All results not taken at a scheduled timepoint for other data types (eg, clinical laboratory 
parameters) are unscheduled. Unscheduled readings are labelled as ‘Unscheduled’ in the listings. 
Because unscheduled readings are not associated with any scheduled timepoint, they are 
excluded from all summaries (with the exception that they may be used as baseline, as stated in 
Section 10.1.1). 
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10.2 Demographics, Baseline Characteristics and Subject Disposition 
The demographic variables age, sex, race, ethnicity, body weight, height, and body mass index 
(BMI) will be listed and summarized by part (under Safety population). 
Subject disposition will be listed and summarized by part (under Safety population). 
10.3 Pharmacokinetic Assessment 
10.3.1 Pharmacokinetic Analysis 
Part 1 
The following PK parameters will be determined where possible from the plasma concentrations 
of risdiplam and respective metabolites on Days 1 and 14, as appropriate, using 
non-compartmental methods performed using Phoenix WinNonlin (Version 8.1 or higher): 
Parameter 
Definition 
AUCtau 
area under the plasma concentration-time curve from time zero to the end 
of the dosing interval (Days 1 and 14 for risdiplam and metabolites, as 
applicable, only) 
Cmax 
maximum observed plasma concentration 
Ctrough 
trough observed plasma concentration (risdiplam and metabolites, as 
applicable, only) 
Tmax 
time of the maximum observed plasma concentration 
t1/2 
apparent plasma terminal elimination half-life (where possible) 
z 
apparent terminal elimination rate constant 
CLss/F 
apparent total plasma clearance at steady state calculated as Dose/AUCtau 
(Day 14, risdiplam only) 
ARAUC 
accumulation ratio for AUC calculated as Day 14 AUCtau/Day 1 AUCtau 
(risdiplam only) 
ARCmax 
accumulation ratio for Cmax calculated as the Day 14 Cmax/ Day 1 Cmax 
(risdiplam only) 
MRAUC 
metabolite:parent ratio of AUC (as applicable) 
MRCmax 
metabolite:parent ratio of Cmax (as applicable) 
Part 2 
The following PK parameters will be determined where possible from the plasma concentrations 
of risdiplam (Days 3 and 16) or midazolam (Days 1 and 15) and respective metabolites, as 
appropriate, using non-compartmental methods performed using Phoenix WinNonlin 
(Version 8.1 or higher): 
Parameter 
Definition 
AUClast 
area under the plasma concentration-time curve from time zero to the 
time of last quantifiable concentration (tlast), calculated using the linear 
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trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations (midazolam and metabolites, as applicable, 
only) 
AUCtau 
area under the plasma concentration-time curve from time zero to the end 
of the dosing interval (Days 3 and 16 for risdiplam and metabolites, as 
applicable, only) 
AUCinf 
area under the concentration-time curve from time zero extrapolated to 
infinity (Day 1 for midazolam and metabolites, where possible) 
Cmax 
maximum observed plasma concentration 
Ctrough 
trough observed plasma concentration (risdiplam and metabolites, as 
applicable, only) 
Tmax 
time of the maximum observed plasma concentration 
tlast 
time of last quantifiable plasma concentration (midazolam and 
metabolites, as applicable, only) 
t1/2 
apparent plasma terminal elimination half-life (where possible) 
z 
apparent terminal elimination rate constant 
CL/F 
apparent total plasma clearance after oral administration calculated as 
Dose/AUCinf (Days 1 and 15, midazolam only) 
CLss/F 
apparent total plasma clearance at steady state on Day 16 (risdiplam only) 
ARAUC 
accumulation ratio for AUC calculated as Day 16 AUCtau/Day 3 AUCtau 
(risdiplam only); Day 3 corresponds to the first dose of risdiplam in Part 
2 
ARCmax 
accumulation ratio for Cmax calculated as the Day 16 Cmax/Day 3 Cmax 
(risdiplam only); Day 3 corresponds to the first dose of risdiplam in Part 
2 
MRAUC 
metabolite:parent ratio of AUC (as applicable) 
MRCmax 
metabolite:parent ratio of Cmax (as applicable) 
Additional PK parameters may be determined where appropriate. If AUCinf cannot be properly 
estimated, AUClast (area under the plasma concentration-time curve from time zero to the time of 
last quantifiable concentration) will be reported in addition to the associated parameters tlast and 
Clast. In addition, an alternate partial AUC from time zero to a common postdose time may be 
calculated. 
The PK analysis will, where possible, be carried out using actual postdose times recorded in the 
raw data. If actual times are missing, nominal times may be used.  
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
Clast (if applicable), Cmax, Ctrough, and Tmax will be obtained directly from the plasma 
concentration-time profiles. 
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Sponsor Reference: BP41361 
 
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For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest Tmax will be reported. 
The metabolic ratios (MRAUC and MRCmax) will be calculated as follows: 
drug
parent
AUC
metabolite
AUC
MR
0
0
AUC





 
drug
parent
C
metabolite
C
MR
max
max
max
C

 
MRAUC and MRCmax) will be corrected for molecular weight (MW), with the MWs as follows: 
risdiplam: 401.46 g/mol 
metabolite M1: 417.5 g/mol 
AUClast or other common partial area may be used to determine metabolite ratios (MRAUC) if 
AUCinf cannot be calculated. 
10.3.1.1 Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis 
● Concentration values that are below the level of quantification (BLQ) will be set to zero, with 
defined exceptions as follows; 
○ Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis and graphical displays. 
○ If there are late positive concentration values following 2 BLQ concentration values in the 
apparent terminal phase, these values will be evaluated. If these values are considered to be 
anomalous, they will be set to missing. 
○ If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis. 
○ If a predose concentration is missing for the first dose, these values may be set to zero by 
default. 
10.3.1.2 Criteria for the Calculation of an Apparent Terminal Elimination Half-Life 
10.3.1.2.1 Number of Data Points 
● At least 3 data points will be included in the regression analysis and must not include Cmax. 
10.3.1.2.2 Goodness of Fit 
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Sponsor Reference: BP41361 
 
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● When assessing terminal elimination phases, the adjusted coefficient of determination for 
exponential fit (R2 adjusted) will be used as a measure of the goodness of fit of the data points 
to the determined line.  
● Lambda z (λz) derived parameters (t1/2, AUCinf, CL/F, andCLss/F) will only be calculated if 
the R2 adjusted value of the regression line is ≥0.7. 
10.3.1.2.3 Period of Estimation 
● Apparent terminal elimination half-life will be calculated over a time period of at least 2 
half-lives, where possible. 
● Where t1/2 is estimated over a time period of less than 2 half-lives, the AUCinf, t1/2, and CL/F 
values will not be reported. 
10.3.1.3 Calculation of Area Under the Concentration-time Curve 
● The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with at 
least one of these concentrations following Cmax. 
● AUC values will be calculated using the linear trapezoidal rule for increasing concentrations 
and the logarithmic rule for decreasing concentrations. 
● For any partial AUC determination (if required), nominal time will generally be used for the 
end of the interval. Actual times for partial AUC intervals will be used for all other time 
points within a certain interval as appropriate. 
 AUCinf values where the percentage extrapolation is <20% will be reported. Where the 
percentage extrapolation exceeds 20% the t1/2, AUCinf, and CL/F values will not be derived. 
● If AUCinf cannot be determined for all subjects in Part 2, an alternative AUClast, Clast and tlast 
will be used in the assessment of the effect of multiple oral doses of risdiplam on the PK of a 
single oral dose of midazolam. 
10.3.1.4 Anomalous Values 
● If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in the raw data and 
the CSR. 
● Embedded BLQ values may be considered anomalous depending on the route of 
administration and the characteristics of the drug. 
● PK parameter data associated with quantifiable predose values >5% of Cmax may be excluded 
from the summary statistics and statistical analysis at the discretion of the Pharmacokineticist. 
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10.3.2 Presentation of Pharmacokinetic Data 
10.3.2.1 Presentation Pharmacokinetic Plasma Drug Concentration Data 
● The following rules will be applied if there are values that are BLQ or if there are missing 
values (e.g., no result [NR]) in plasma concentration data series to be summarized. 
○ For the calculation of summary statistics, BLQ values will be set to zero. 
○ If an embedded BLQ value is considered anomalous within the concentration-time profile, 
this value will be excluded from the summary statistics. 
○ Where there is NR, these will be set to missing. 
○ If there are less than 50% values in the data series have measurable concentrations 
(excluding BLQ values), only N will be presented. The other summary statistics will be 
denoted as not calculated (NC). 
○ If all the values are BLQ, then all summary statistics will be denoted as NC. 
○ If the value of the arithmetic mean or median is below the lower limit of quantification, 
mean and/or median, the SD, geometric mean, and geometric CV% will be denoted as NC. 
10.3.2.2 Presentation Pharmacokinetic Parameters 
● For the calculation of summary statistics of PK parameters, all NR and NC values in a data 
series will be set to missing. 
● The AUC values will be set to NC if they have been calculated using fewer than 3 
concentrations, and/or 3 concentrations if the last is Cmax. 
The PK parameters and concentrations will be listed and summarized by part, analyte, profile 
day, and treatment. 
Concentrations will be graphically represented with an arithmetic mean (+SD) plot and a 
concentration-time profile by subject and for all subjects (linear scale and semi-logarithmic 
scale) by part, analyte, profile day, and treatment. Any embedded BLQ value (between 2 
quantifiable concentrations) and BLQ values following the last quantifiable concentration in a 
profile will be set to missing for the purposes of graphical displays. 
10.3.3 Pharmacokinetic Statistical Methodology 
The primary analysis is the evaluation of the PK of midazolam in combination with risdiplam 
(and metabolite M1, as appropriate) (‘Test’ group), compared to midazolam alone (‘Reference’ 
group). 
No formal statistical analyses are planned for Part 1. 
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Sponsor Reference: BP41361 
 
Version 1, Final 1: 2 October 2019 
 
Page 16 of 19 
 
In Part 2, the effect of multiple oral doses of risdiplam on the PK of a single oral dose of 
midazolam (and its metabolite[s] as appropriate) will be explored using an analysis of variance4 
applied to the log-transformed PK parameters Cmax and AUCinf (or, if AUCinf cannot be properly 
estimated, AUClast or an alternate partial AUC from time zero to a common post-dose time, 
AUClast). The model will include treatment as a fixed effect and subject as a random effect. From 
the model estimates, the geometric mean ratios (midazolam in combination with risdiplam versus 
midazolam alone) will be derived together with corresponding two-sided 90% confidence 
intervals. 
10.4 Safety and Tolerability Assessments 
10.4.1 Adverse Events 
A baseline sign and symptom is defined as an AE that starts after the subject has provided 
written informed consent and that resolves prior to the first dosing occasion, or an AE that starts 
prior to the first dosing occasion and does not increase in severity after dosing. As per the 
protocol, the only baseline sign and symptoms recorded should be serious adverse events (SAEs) 
caused by a protocol-mandated intervention (eg, SAEs related to invasive procedures such as 
biopsies). A treatment-emergent AE (TEAE) is defined as an AE that occurs postdose or that is 
present predose and becomes more severe postdose. 
For Part 2 a TEAE occurring: 
● during or after Day 1 dosing and prior to predose Day 3 will be assigned to ‘2 mg midazolam’ 
treatment 
● during or after Day 3 dosing and prior to predose Day 15 will be assigned to ‘8 mg risdiplam 
QD’ treatment 
● during or after Day 15 dosing will be assigned to ‘2 mg midazolam and 8 mg risdiplam QD’ 
treatment 
Each AE will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
All AEs will be listed. In the overall summary table, the TEAEs will be summarized by part, 
treatment, intensity, and relationship to the study treatment. The frequency (the number of 
TEAEs, the number of subjects experiencing a TEAE, and the percentage of subjects 
experiencing a TEAE) of TEAEs will be summarized by part, treatment, MedDRA system organ 
class, and preferred term. The frequency TEAE tables will be presented for all causalities and for 
TEAEs considered possibly related and related to the study treatment. Serious TEAEs will be 
tabulated separately. For any AEs that change severity ratings the AE will be included only once 
under the maximum severity rating in the summaries. 
10.4.2 Clinical Laboratory Parameters 
All clinical laboratory data will be listed and values outside the clinical reference ranges will be 
flagged. 
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Clinical chemistry, hematology, and coagulation data together with changes from baseline, will 
be summarized by part and timepoint. 
In addition, all clinical chemistry, hematology, coagulation, and urinalysis data outside the 
clinical reference ranges will be listed by parameter and timepoint. 
Shift from baseline tables will be provided for clinical chemistry, hematology, and coagulation 
data. Additionally, subjects with elevated post-baseline AST or ALT levels will be summarized. 
10.4.3 Vital Signs 
All vital signs will be listed and values outside the clinical reference ranges will be flagged. The 
following reference ranges will be used for vital signs data: 
 Systolic Blood Pressure: 90 – 140 mmHg 
 Diastolic Blood Pressure: 60 – 90 mmHg 
 Pulse Rate: 40 – 100 bpm 
 Body Temperature: 35.5 – 37.5 oC 
The vital signs data, together with changes from baseline, will be summarized by part, parameter 
and timepoint. Figures of mean vital signs profiles will be presented. 
10.4.4 Electrocardiogram 
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the QT 
interval calculated using the Fridericia’s correction (QTcF), the PR and QT intervals, RR 
interval, the QRS duration, and heart rate. 
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Covance Study: 8406533 
 
Sponsor Reference: BP41361 
 
Version 1, Final 1: 2 October 2019 
 
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All ECG data will be listed and values outside the clinical reference ranges will be flagged. The 
following reference ranges will be used for ECG data: 
 PR Interval: 120 – 200 ms 
 QRS Duration: 80 – 120 ms 
 QT Interval: 200 – 500 ms 
 QTcF Interval: 300 – 450 ms 
 RR Interval: 600 – 1500 ms 
 Heart Rate: 40 – 100 bpm 
The ECG data, together with changes from baseline, will be summarized by part, parameter and 
timepoint. Figures of mean ECG profiles will be presented. 
10.4.5 Previous and Concomitant Medications 
Previous medication will be defined as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that starts after the first dose or starts but does not end 
prior to the first dose. 
Previous and concomitant medications will be coded using WHODrug. 
Previous medications will be listed. 
Concomitant medications will be listed and summarized by part. The frequency (the number of 
treatments, the number of subjects receiving a concomitant medication, and the percentage of 
subjects receiving a concomitant medication) of concomitant medications will be summarized by 
part, treatment, medication, and preferred term. 
10.4.6 Other Assessments 
Medical history data will be listed. 
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analysed. 
10.4.7 Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
11  
INTERIM ANALYSES 
No formal interim analysis is planned. Data from Part 1 will be evaluated before the start of 
Part 2, and the dose selection for Part 2 will be based on Part 1 data. 
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Covance Study: 8406533 
 
Sponsor Reference: BP41361 
 
Version 1, Final 1: 2 October 2019 
 
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The decision to proceed to Part 2 will be made following review of all safety and tolerability 
information collected up to 48 hours after last study drug administration (including AEs, ECGs, 
vital signs, and clinical laboratory test results), and of all PK data collected up to (and including) 
24 hours after last study drug administration in Part 1 from a minimum of 4 participants. 
12  
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
There were no changes from the protocol-specified statistical analyses. 
13  
DATA PRESENTATION 
13.1 Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.” 
14  
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
3. 
, et al. The bioavailability and pharmacodynamics of midazolam (RO 
21-3981 and its 1’-hydroxymethyl midazolam metabolite (RO 21-6347) following single 
dose intravenous, intramuscular, oral solution, and oral tablet administration to normal 
subjects. Research Report N-36884, October 9, 1982. 
4. Snedecor GW, Cochran WG.  Statistical Methods (8th edition).  Iowa: Iowa State Univ Press, 
1989: 217-253. 
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