NCT02867709

Study ID: UBR-MD-02

1. Title Page

STATISTICAL ANALYSIS PLAN

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Single Attack Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute Treatment of Migraine

Protocol Number:
UBR-MD-02 Amendment 3
Development Phase:
3
Product Name:
Ubrogepant
Study Statistician:
Sponsor:

2. Table of Contents

1. Title Page ..... 1
2. Table of Contents ..... 2
   2.1 List of Tables ..... 3
   2.2 List of Figures ..... 5
3. List of Abbreviations and Definition of Terms ..... 6
4. Introduction ..... 8
   4.1 Study Design Summary ..... 8
   4.2 Study Objectives and Endpoints ..... 9
5. Statistical Methodology and Study Endpoints ..... 18
   5.1 Statistical Methods Planned in the Protocol and Determination of Sample Size ..... 18
   5.1.1 Statistical and Analytical Plans ..... 18
   5.1.1.1 Common Conventions ..... 18
   5.1.1.2 Demographics ..... 31
   5.1.1.3 Efficacy and
   5.2 Changes in the Conduct of the Study or Planned Analyses ..... 54
   5.2.1 Changes in the Conduct of the Study ..... 54
   5.2.2 Changes to Analyses Prior to Database Lock ..... 54
6. Data Handling and Analysis Conventions ..... 55
   6.1 Study Treatment Conventions ..... 55
   6.1.1 Analysis Days ..... 55
   6.1.2 Missing/Incomplete Treatment End Date ..... 55
   6.2 Analysis Visit Windows ..... 55
   6.2.1 Efficacy ..... 55
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Table 5-27 Assumed Response Rates and Estimated Power for Primary and Secondary Efficacy Endpoints ..... 53
Table 6-1 Analysis Day Definitions ..... 55
Table 6-2 Efficacy Analysis Visit Definitions ..... 55
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2.2 List of Figures

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Figure 5-5 Determination of sustained pain freedom from 2 to 24 hours after the initial dose ..... 27

3. List of Abbreviations and Definition of Terms

4. Introduction

1. Study overview
2. Statistical Methodology and Study Endpoints
3. Data Handling and Analysis Conventions

4.1 Study Design Summary

Study Treatment Groups: Ubrogepant 25 mg , ubrogepant 50 mg
Controls: Ubrogepant placebo
Dosage/Dose Regimen: Study participants will have up to 60 days to treat a single qualifying migraine attack of moderate or severe headache pain intensity at home. Participants have the option to take a second dose of investigational product (IP) or rescue medication if the participant has either a nonresponding migraine or a migraine recurrence. Participants who are randomized to ubrogepant arms will be randomly assigned at the Randomization Visit (Visit 2) to active treatment or placebo ( ) for the blinded optional second dose. Participants randomized to the placebo arm will receive placebo for their blinded optional second dose.
Randomization Participants will be randomized to 1 of the following 3 treatment groups: placebo, ubrogepant 25 mg , or ubrogepant 50 mg .

4.2 Study Objectives and Endpoints

Table 4-1 Study Objectives and Corresponding Endpoints

Objectives

Endpoints

Primary - [PO1] To compare the efficacy, safety, and tolerability of 2 doses of ubrogepant ( 25 and 50 mg ) with placebo in participants with a single migraine attack

Primary Efficacy Endpoints The coprimary efficacy parameters for the United States of America (US) are as follows: - [P1] Pain freedom (PF) at 2 hours after the initial dose, defined as a reduction in headache severity from moderate/severe at baseline to no pain, at 2 hours after the initial dose - [P2] Absence of the most bothersome migraine-associated symptom (the most bothersome migraine-associated symptom will be identified at baseline for each participant) at 2 hours after the initial dose. Secondary Efficacy Endpoints The secondary efficacy parameters for the US are: - [S1] Pain relief (PR) at 2 hours after the initial dose, defined as the reduction of a moderate/severe migraine headache to a mild headache or to no headache, at 2 hours after the initial dose - [S2] Sustained pain relief (SPR) from 2 to 24 hours after the initial dose, defined as pain relief with no administration of either rescue medication or the second dose of IP, and with

5. Statistical Methodology and Study Endpoints

5.1 Statistical Methods Planned in the Protocol and Determination of Sample Size

5.1.1 Statistical and Analytical Plans

5.1.1.1 Common Conventions

5.1.1.1.1 Analysis Populations

5.1.1.1.2 Study Treatments

• Placebo
• Ubrogepant 25 mg
• Ubrogepant 50 mg

5.1.1.1.3 Statistical Methodology

Table 5-2 Statistical Methodology

	Methodology	Description
M1	Categorical counts	- Number of participants in individual categories - Participants with qualifying event counted once per individual category
M2	Categorical descriptives	- Number and percentage of participants in individual categories - Participants with qualifying event counted once per individual category - N1 if proportion denominator number of participants in the population (standard percentage denominator) - N1 = participants with non-missing baseline value
M5	Continuous descriptives	- N1, mean, standard deviation (SD), median, minimum, maximum - N1 = participants with non-missing value
M6	CFB descriptives	- Continuous descriptives for baseline, postbaseline, and change from baseline (CFB) values - N1 = participants with non-missing values at both baseline and the specified postbaseline analysis visit
M8	Responder	- Categorical descriptives using proportions for responders and nonresponders - Nonresponders include: - Participants who do not meet responder criteria - N1 = all participants unless otherwise specified
M10	Logistic regression model	- Measures the relationship between the binary categorical dependent variable (responder or nonresponder) and independent variables - Independent variables for initial dose: - treatment group (placebo, ubrogepant 25 mg , ubrogepant 50 mg ) - historical triptan response (triptan responder, triptan insufficient responder, or triptan naïve) - use of medication for migraine prevention (yes, no) - baseline headache severity (moderate or severe)

change from baseline; analysis of covariance.
Raw and derived data listings will be provided, and will be fully defined in the table, figure, and data listing specification document.

5.1.1.1.4 Missing Data

Table 5-3 Missing Data Handling by Endpoint Type

Parameter type	Timing	Missing Data Handling
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Responder	Treatment Period	- If missing headache severity, migraine-associated symptoms, satisfaction with study medication, or functional disability scale at scheduled postdose time points, use LOCF - Sensitivity analysis for the primary efficacy endpoints is to impute participants with missing data at 2 hours as nonresponders, provided that the participant has at least 1 postdose value before 2 hours after the initial dose
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Figure 5-5 Determination of sustained pain freedom from 2 to 24 hours after the initial dose

Figure 5-6 Determination of sustained pain relief from 2 to 24 hours after the initial dose

Figure 5-7 Determination of sustained pain freedom from 2 to 48 hours after the initial dose

Figure 5-8 Determination of sustained pain relief from 2 to 48 hours after the initial dose

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5.1.1.2 Demographics

5.1.1.2.1 Analysis Populations

5.1.1.2.2 Participant Disposition

5.1.1.2.3 Protocol Deviations

5.1.1.2.4 Demographics

5.1.1.2.5 Baseline Characteristics

5.1.1.2.6 Medical History

5.1.1.2.7 Migraine History

5.1.1.2.8 Prior and Concomitant Medications

5.1.1.3 Efficacy and Pharmacokinetic Analyses

Table 5-12 Efficacy Assessments

Assessment/Term	Description
Rating of Headache Severity	Headache severity will be subjectively rated by the participant at predefined timepoints (predose and , and 48 hours after the initial dose) on a scale from no pain to severe pain: - No pain - Mild pain - Moderate pain - Severe pain
Use of Rescue Medication	Any rescue medication taken within 48 hours after treating their migraine attack with IP, in addition documenting the date and time that the rescue medication was taken. - Recorded by participants in e-diary
Use of Optional Second Dose and Recurrence of Headache Pain	Optional second dose of IP due to inadequate response to their initial dose of IP. Date and time of the second dose will be reported, as well as pain severity and absence or presence of migraine-associated symptoms at the time the second dose is taken and 2 hours after taking the second dose. The incidence of recurrence in participants who had pain relief and pain freedom at 2 hours after the initial dose will be collected. - Recorded by participants in e-diary
Migraine-associated symptoms	Absence or presence of migraine-associated symptoms: photophobia, phonophobia, nausea, and vomiting - Completed by the participant in e-diary

5.1.1.3.1 Endpoints for US

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Table 5-15 EU Analyses

5.1.1.3.4 Multiple Comparisons Procedure for Primary and Secondary Endpoints

Figure 5-9 Multiple Comparisons Procedure for the US

5.1.1.4.1 Study Treatment Exposure and Compliance

Treatment compliance to the first dose of study medication will not be calculated as participants are only to take 1 tablet.

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5.1.1.5 Subgroup Analyses

• PF at 2 hours after initial dose
• Absence of the most bothersome migraine-associated symptom at 2 hours after initial dose (US only)
• Time to PF within 48 hours after the initial dose
• Time to absence of the most bothersome migraine-associated symptom within 48 hours after the initial dose (US only)

5.1.1.6 Interim Analyses

Not applicable.

5.2 Changes in the Conduct of the Study or Planned Analyses

5.2.1 Changes in the Conduct of the Study

5.2.2 Changes to Analyses Prior to Database Lock

6. Data Handling and Analysis Conventions

6.1 Study Treatment Conventions

6.1.1 Analysis Days

6.1.2 Missing/Incomplete Treatment End Date

6.2 Analysis Visit Windows

6.2.1 Efficacy

6.4 Imputed Value Listing Conventions

7. References

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Single Attack Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute Treatment of Migraine

STATISTICAL ANALYSIS PLAN AMENDMENT
SUMMARY OF CHANGES

Confidentiality Statement

1 AMENDMENT #1 TO STATISTICAL ANALYSIS PLAN for UBR-MD-02

1.1 Introduction

• Adding 9 other efficacy endpoints in Table 4-1 Study Objectives and Corresponding Endpoints
• Adding proportional odds model analysis in Table 5-2 Statistical Methodology
• Updating missing data handling for headache recurrence endpoints
• Adding 9 endpoints in Table 5-14 US Analyses and 4 endpoints in
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• Updating Figure 5-9 Multiple Comparisons Procedure for the US
  
• Updating Section 5.1.1.4.1 Study Treatment Exposure and Compliance
  

  

• Adding subgroup analyses in Section 5.1.1.5 Subgroup Analyses
  

  

• Minor editorial changes

1.2 Global Changes

1.3 Sections Deleted

1.4 Sections Added

1.5 Revisions

1.5.1 Table 4-1, Study Objectives and Corresponding Endpoints (Pages 11-14)

Rationale: This section has been amended to reflect adding 9 other efficacy endpoints to the list of other efficacy endpoints.

1.5.2 Table 5-2, Statistical Methodology (Page 20-21)

Rationale: This table has been amended to add the proportional odds model for the analysis of pain severity at 2 hours after the initial dose.

1.5.3 Section 5.1.1.1.4, Missing Data (Pages 21-31)

The missing data section now reads as follows:

Table 5-3 Missing Data Handling by Endpoint Type

A conservative approach will used to resolve the incompatibility between the answers to the headache recurrence questions at the 24 - and 48 -hour time points by setting the answer to the recurrence question at the 48-hour time point the same as the answer to the recurrence question at the 24-hour time point, when the 24-hour time point recurrence question indicates headache recurrence between 2 and 24 hours but the 48-hour time point recurrence question indicates either no or a less severe headache recurrence between 2 and 48 hours.

Figure 5-51 Determination of sustained pain freedom from 2 to 24 hours after the initial dose

Figure 5-6x2 Determination of sustained pain relief from 2 to 24 hours after the initial dose

Figure 5-73 Determination of sustained pain freedom from 2 to 48 hours after the initial dose

Figure 5-84 Determination of sustained pain relief from 2 to 48 hours after the initial dose

1.5.4 Table 5-14, US Analyses

The US Analyses and

tables now reads as follows:

1.5.5 Section 5.1.1.3.4 Multiple Comparisons Procedure for Primary and Secondary Endpoints (Pages 46-48)

The section now reads as follows:

• The secondary endpoints will be tested in the same order as they appear in the list of secondary endpoints, except for the 子 migraine-associated symptoms, photophobia and phonophobia, which will be treated at the same level to allow the recycling of weights among the 2 子 symptom endpoints. Recycling of weights between the 2 doses from nausea to pain freedom is also allowed.

Figure 5-95 Multiple Comparisons Procedure for the US

Figure 5-95 Multiple Comparisons Procedure for the US

1.5.6 Section 5.1.1.4.1 Study Treatment Exposure and Compliance (Page 48)

This section now reads as follows:

Treatment compliance to the first dose of study medication will not be calculated as participants are only to take 1 tablet.

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1.5.10Section 5.1.1.5 Subgroup Analyses

• PF at 2 hours after initial dose
• Absence of the most bothersome migraine-associated symptom at 2 hours after initial dose (US only)
• Time to PF within 48 hours after the initial dose
• Time to absence of the most bothersome migraine-associated symptom within 48 hours after the initial dose (US only)