A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Of Navitoclax In Combination With Ruxolitinib Versus Ruxolitinib In Subjects With Myelofibrosis (TRANSFORM-1)
Phase: PHASE3
Conditions: Myelofibrosis (MF)
Sponsor: AbbVie



  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
10
2.1
BACKGROUND AND RATIONALE
10
2.2
BENEFITS AND RISKS TO SUBJECTS
11
3
OBJECTIVES AND ENDPOINTS
12
3.1
PRIMARY ENDPOINT
13
3.2
SECONDARY ENDPOINTS
13
3.3
EXPLORATORY ENDPOINTS
14
3.4
SAFETY ENDPOINTS
15
3.5
PHARMACOKINETIC ENDPOINTS
15
3.6
BIOMARKER RESEARCH ENDPOINTS
15
4
INVESTIGATIONAL PLAN
15
4.1
OVERALL STUDY DESIGN AND PLAN
15
4.2
DISCUSSION OF STUDY DESIGN
17
5
STUDY ACTIVITIES
19
5.1
ELIGIBILITY CRITERIA
19
5.2
CONTRACEPTION RECOMMENDATIONS
22
5.3
PROHIBITED/CAUTIONARY MEDICATIONS AND THERAPY
24
5.4
PRIOR AND CONCOMITANT THERAPY
25
5.5
SUBJECT DISCONTINUATION FROM STUDY DRUG TREATMENT AND DISCONTINUATION OF STUDY
26
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
28
5.7
POST-TREATMENT FOLLOW UP
29
5.8
SURVIVAL FOLLOW UP
29
5.9
STUDY DRUG
29
5.10 RANDOMIZATION/DRUG ASSIGNMENT
30
5.11 PROTOCOL DEVIATIONS
31
5.12 DATA MONITORING COMMITTEE
31
Page 2 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6
SAFETY CONSIDERATIONS
32
6.1
COMPLAINTS AND ADVERSE EVENTS
32
6.2
TOXICITY MANAGEMENT
36
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
41
7.1
STATISTICAL AND ANALYTICAL PLANS
41
7.2
DEFINITION FOR ANALYSIS POPULATIONS
41
7.3
STATISTICAL ANALYSES FOR EFFICACY
42
7.4
STATISTICAL ANALYSES FOR SAFETY
43
7.5
INTERIM ANALYSIS
43
7.6
OVERALL TYPE I ERROR CONTROL
44
7.7
SAMPLE SIZE DETERMINATION
44
8
ETHICS
44
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
44
8.2
ETHICAL CONDUCT OF THE STUDY
45
8.3
SUBJECT CONFIDENTIALITY
45
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
45
10 DATA QUALITY ASSURANCE
45
11 START AND COMPLETION OF THE STUDY
46
12 REFERENCES
46
LIST OF TABLES
TABLE 1.
DOSE ADJUSTMENT GUIDELINES FOR THROMBOCYTOPENIA AND NEUTROPENIA
39
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMA
17
Page 3 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
48
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
52
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
53
APPENDIX D.
ACTIVITY SCHEDULE
54
APPENDIX E.
WORLD HEALTH ORGANIZATION DIAGNOSTIC CRITERIA FOR PRIMARY MYELOFIBROSIS
60
APPENDIX F.
DYNAMIC INTERNATIONAL PROGNOSTIC SCORING SYSTEM (DIPSS) AND DIPSS PLUS (DIPSS+) 
FOR SURVIVAL IN PRIMARY MYELOFIBROSIS
61
APPENDIX G.
SAMPLE LIST OF EXCLUDED AND CAUTIONARY MEDICATIONS
62
APPENDIX H.
PROTOCOL SUMMARY OF CHANGES
65
APPENDIX I.
OPERATIONS MANUAL
67
Page 4 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The exploratory objectives are: 

To evaluate responses to navitoclax and ruxolitinib versus 
ruxolitinib in subjects with high molecular risk (HMR) 
mutations.

To evaluate the effect of navitoclax in combination with 
ruxolitinib on progression-free survival (PFS).

To evaluate the effect of navitoclax in combination with 
ruxolitinib on the frequency of mutated alleles.

Exploration of biomarkers predictive of navitoclax activity 
and response may be performed.  Potential analysis may 
include, but will not be limited to, the evaluation of:

BCL-2 family profiling

Inflammatory cytokine reduction

Mutational status.
Endpoints
Primary Efficacy Endpoint:

At least 35% reduction in spleen volume at Week 24 from 
baseline (SVR35W24) as measured by magnetic resonance 
imaging (MRI) or computed tomography (CT) scan, per 
International Working Group (IWG) criteria.
Secondary Efficacy Endpoints:

Change in total symptom score (TSS) at Week 24 from 
baseline as measured by Myelofibrosis Symptom 
Assessment Form (MFSAF) v4.0

At least 35% reduction in spleen volume from baseline 
(SVR35) as measured by MRI or CT scan, per IWG criteria

Duration of SVR35

Change in fatigue at Week 24 from baseline as measured 
by the PROMIS Fatigue SF 7a

Change in physical functioning at Week 24 from baseline, 
as measured by the Physical functioning domain of the
European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life questionnaire (QLQ)-C30

Anemia response per IWG criteria

Overall survival

Leukemia-free survival

Reduction in grade of bone marrow fibrosis from baseline 
as measured by the European consensus grading system
Exploratory Endpoints:

At least 50% reduction in palpable splenomegaly from 
baseline per IWG criteria

Red blood cell (RBC) transfusion during study drug 
treatment
Page 6 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Change in quality of life from baseline as measured by the 
global health status/quality of life domain of the 
EORTC QLQ-C30

Change in the summary score for the EORTC QLQ-C30 
from baseline

Progression-free survival per IWG criteria

Change in frequency of allelic mutations from baseline

Change in EQ-5D-5L from baseline

Change in impacts associated with fatigue from baseline as 
assessed by the PROMIS Fatigue 7a impact items

Change in fatigue-related symptoms from baseline as assessed 
by the PROMIS Fatigue 7a symptom items

Translational biomarkers and correlation with clinical 
outcomes

Overall response of clinical improvement per IWG criteria

At least 50% reduction in TSS at Week 24 from baseline 
(TSS50W24)

Time to first TSS50

Duration of TSS50

TSS response rate at any time based on meaningful change 
threshold (MCT)

Time to first TSS response

Duration of TSS response
Safety Endpoints:
Safety endpoints will be based on the following evaluations:  adverse 
event (AE) monitoring, physical examinations, vital sign measurements, 
electrocardiogram (ECG) variables, and clinical laboratory testing 
(hematology and chemistry).
Pharmacokinetic Endpoints:
Sparse pharmacokinetic (PK) samples will be collected at specified time 
points.  Individual plasma concentrations of navitoclax from sparse PK 
sampling will be tabulated and summarized.  Population PK parameters 
of navitoclax such as apparent oral clearance (CL/F) and apparent 
volume of distribution (V/F) may be estimated using non-linear mixed 
effects model.
Biomarker Endpoints:
Biospecimens (whole blood, plasma, bone marrow aspirate, and/or 
bone marrow core) will be collected at specified time points 
throughout the study to evaluate known and/or novel disease-related 
or drug-related biomarkers in circulation or at tissue sites.  Some of 
these samples may be optional.  Types of biomarkers may include 
nucleic acids, proteins, lipids, and/or metabolites, either free or in 
association with particular cell types.  The analyses may include but are 
not limited to mutational status, BCL-2 family profiling, and 
inflammatory cytokine reduction.
Page 7 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Myelofibrosis (MF) is an acquired clonal Philadelphia chromosome negative myeloproliferative 
neoplasm that is characterized by constitutional symptoms, splenomegaly, an increased risk of 
transformation to acute myeloid leukemia, and a shortened life expectancy.1  Although Janus kinase 2 
(JAK2) inhibitors such as ruxolitinib are approved in several geographic regions, these therapies are 
insufficient for most patients and better treatments are needed.  Whilst therapy with ruxolitinib induces 
improvement in splenomegaly and disease-related symptoms, it does not eradicate the malignant 
clones and may induce modest improvement in the degree of bone marrow fibrosis in a small subset of 
patients treated.2,3  Patients who stop ruxolitinib rapidly become symptomatic, some patients do not 
respond to ruxolitinib, and others develop secondary resistance, thus ruxolitinib alone is typically 
insufficient for sustained disease control.4  Current therapies, other than hematopoietic stem cell 
transplantation (HSCT) which is only accessible to 5 to 10% of patients, are not able to control all the 
clinical manifestations of MF.  Therefore, new treatments including combination therapies with 
ruxolitinib as the backbone may provide additional benefits and improve clinical outcomes in these 
patients.
Navitoclax binds to and inhibits antiapoptotic B-cell lymphoma-2 (BCL-2) family proteins with high 
affinity to BCL-XL, BCL-2 and BCL-W.  Thus, it selectively induces program death in cells that have a BCL-2 
family protein ratio shifted towards survival as observed in human cell lines derived from small cell lung 
carcinomas and lymphoid malignancies (concentration required for 50% effect [EC50] ≤ 1 μM).  
Additionally, navitoclax potently enhances the cytotoxicity of both chemotherapy and radiation in cells 
derived from multiple, major tumor types, regardless of whether single-agent efficacy is achieved.
Clinical studies conducted to date have assessed safety, pharmacokinetics, and initial efficacy of 
navitoclax as a single agent and as combination therapy in subjects with hematological malignancies and 
subjects with solid tumors.  The monotherapy recommended Phase 2 dose (RPTD) has been determined 
as 250 mg in chronic lymphocytic leukemia (CLL) (with a 100 mg lead-in period prior to Cycle 1) and 
325 mg under the continuous dosing schedule in small cell lung cancer and other lymphoid malignancies 
(excluding CLL; with a 150 mg lead-in period prior to Cycle 1), although the starting dose was reduced to 
250 mg in lymphoid malignancies as this was found to be more tolerable.5-8
Preclinical data suggest that navitoclax may overcome JAK2 resistance, resensitizing cells to JAK2 
inhibition from ruxolitinib, and therefore may provide disease-modifying therapy in subjects with 
primary myelofibrosis (PMF) and secondary myelofibrosis (SMF).6  The combination of navitoclax and 
ruxolitinib in subjects with MF (Study M16-109) has demonstrated efficacy in subjects with persistent 
splenomegaly while receiving treatment with ruxolitinib for at least 12 weeks (AbbVie data on file).  The 
median duration of prior ruxolitinib exposure before initiating navitoclax on Study M16-109 was 
21 months (range 4 to 71 months).  After 24 weeks of treatment with navitoclax and ruxolitinib, 30% of 
subjects achieved spleen volume reduction ≥ 35% (SVR35).  Additionally, spleen responses seem to 
deepen beyond 24 weeks of treatment, and the best overall SVR35 was further improved to 43%.  
Symptom improvements were reported in 65% of subjects with 35% of subjects achieving ≥ 50% 
Page 10 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
reduction from baseline in total symptom score at Week 24.  Additionally, reductions in bone marrow 
fibrosis of ≥ 1 grade were observed in 27% of subjects, suggesting this drug combination may be disease 
modifying.  The safety profile was acceptable with the most common Grade ≥ 3 treatment-emergent AEs 
reported as thrombocytopenia and anemia.  There were no serious adverse events of bleeding.  There 
was 1 treatment-emergent death due to pneumonia that was assessed by the investigator as having no 
reasonable possibility of relationship to navitoclax.
Preliminary pharmacokinetic (PK) data from the Phase 2 M16-109 study of the combination of navitoclax 
and ruxolitinib in subjects with PMF and SMF who have previously received ruxolitinib showed that 
upon co-administration, navitoclax exposures (n = 34) were comparable to historical data in non-MF 
patient population, while ruxolitinib area under the curve from 0 to 12 hours (AUC0-12) (n = 28) was 29% 
lower compared to historical data in MF patients.  The impact of navitoclax on ruxolitinib exposures is 
being evaluated in Study M16-109.
Preliminary data in the Phase 2 M16-109 study of the combination of navitoclax and ruxolitinib in 
subjects with PMF and SMF who have previously received ruxolitinib suggest favorable spleen response 
rates and an acceptable safety profile.  Best on study spleen volume reductions of > 35% have been 
observed in 43% of subjects, with 35% of subjects also achieving a reduction of > 50% in total symptom 
scores.9  The response rates of the combination of navitoclax and ruxolitinib in subjects previously 
treated with ruxolitinib are comparable to those observed with both ruxolitinib and fedratinib in
patients not previously treated.2  These data support further evaluation of this combination in patients 
with MF that have not received prior treatment with a JAK2 inhibitor.  This Phase 3 study is designed to 
evaluate the combination of navitoclax and ruxolitinib versus ruxolitinib in subjects with PMF or SMF 
who have not previously received a JAK2 inhibitor.
Clinical Hypothesis
Navitoclax, when combined with ruxolitinib, is reasonably likely to result in higher SVR35 rates that are 
more durable, greater reductions in total symptom score (TSS), reversal of bone marrow fibrosis, and 
more allelic burden reductions than the current standard treatment, ruxolitinib alone.
2.2 Benefits and Risks to Subjects
Ruxolitinib (a dual Janus kinase 1 [JAK1] and JAK2 inhibitor) and fedratinib (dual JAK2 and FMS-like 
tyrosine kinase 3 [FLT3] inhibitor) are approved by numerous regulatory bodies worldwide for the 
treatment of myelofibrosis.  While the approval of these JAK2 inhibitors has changed the treatment 
landscape for patients with myelofibrosis, their therapeutic remit is aimed at improving symptoms and 
quality of life.  The only treatment modality capable of curing MF is allogenic HSCT.  The applicability of 
HSCT is limited by the inherent risks in this population, with their attendant comorbidities.
Preclinical data suggest that the combination of navitoclax with ruxolitinib may provide 
disease-modifying therapy for patients with PMF or SMF.  Clinical studies (single-agent and combination 
therapy) have assessed the safety, pharmacokinetics and initial efficacy in subjects with hematologic 
malignancies or in subject with solid tumors.
Risks observed in nonclinical and/or clinical studies associated with navitoclax administration are 
thrombocytopenia, lymphopenia, and neutropenia.  Thrombocytopenia has been the primary 
Page 11 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
dose-limiting toxicity.  Navitoclax accelerates apoptosis, rather than lysis, of circulating mature platelets 
whether endogenous or transfused.  This mechanism of action differs from the thrombocytopenia 
caused by conventional chemotherapy (i.e., toxicity to platelets progenitors in the bone marrow) and 
should, therefore, be managed.  Actions are in place in study protocols to mitigate these risks and, when 
medically indicated, to treat these effects; these include appropriate patient selection, careful 
monitoring, and treatment management guidelines.
The most common treatment emergent hematological adverse reactions of any grade with an incidence 
> 10% reported with navitoclax in combination with ruxolitinib (Study M16-109; Cohort 3) in patients 
with MF who have not previously received ruxolitinib are thrombocytopenia, neutropenia, and anemia.  
The most common treatment emergent nonhematological adverse reactions of any grade with an 
incidence ≥ 10% are nausea and diarrhea.
The most common hematological adverse reactions with an incidence > 20% reported with ruxolitinib
monotherapy in patients treated for MF are thrombocytopenia and anemia.  The most common 
nonhematological adverse reactions with an incidence ≥ 15% are bruising, dizziness, headache, and 
diarrhea.  Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma 
have also been reported requiring periodic skin examination.
The preliminary data of the combination of navitoclax and ruxolitinib (Study M16-109) in patients with 
MF who have previously received ruxolitinib for at least 12 weeks with persistent splenomegaly are 
favorable, demonstrating improvement in spleen volume reduction and total symptom score along with 
reduction in bone marrow fibrosis after treatment with current standard of care, and support further 
evaluation of the combination in patients with MF who have not received prior treatment with a JAK2 
inhibitor.
The Sponsor has evaluated the potential risks of study participation during a global or regional epidemic 
or other extreme circumstance and concludes that the potential benefit of the study treatment 
outweighs the additional risk.
For further benefit and risk details, please see the current navitoclax Investigator's Brochure.
Considering the coronavirus disease 2019 (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated.  Subjects receiving navitoclax may be at an increased 
risk for COVID-19 infection or experience serious illness if infected.  Management of these adverse 
events will be made on a case-by-case basis with consideration of benefit/risk by the investigators.  
However, based on the population, the disease being studied, and the anticipation that COVID-19 
related risks are unknown between study subjects and the broader population of subjects receiving 
treatment for myeloproliferative neoplasms, no known change to the benefit/risk balance for subjects in 
this study is expected.
3 OBJECTIVES AND ENDPOINTS
Primary Objective
1.
To evaluate the effect of navitoclax in combination with ruxolitinib on splenomegaly response 
when compared to ruxolitinib in subjects with myelofibrosis (MF).
Page 12 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Secondary Objectives
1.
To evaluate the effect of navitoclax in combination with ruxolitinib on the onset, magnitude, and 
duration of disease response, including total symptom score (TSS), effects on spleen, bone 
marrow fibrosis, and anemia.
2.
To evaluate the effect of navitoclax in combination with ruxolitinib on measures of 
health-related quality of life (HRQoL) including fatigue, and physical functioning.
3.
To evaluate the effect of navitoclax in combination with ruxolitinib on overall survival (OS) and 
leukemia-free survival (LFS).
Exploratory Objectives
1.
To evaluate responses to navitoclax and ruxolitinib in subjects with high molecular risk (HMR) 
mutations.
2.
To evaluate the effect of navitoclax in combination with ruxolitinib on progression-free survival 
(PFS).
3.
To evaluate the effect of navitoclax in combination with ruxolitinib on the frequency of mutated 
alleles.
4.
Exploration of biomarkers predictive of navitoclax activity and response may be performed.  
Potential analysis may include, but will not be limited to, the evaluation of:

BCL-2 family profiling

Inflammatory cytokine reduction

Mutational status.
3.1 Primary Endpoint
At least 35% reduction in spleen volume at Week 24 (SVR35W24) from baseline as measured by magnetic 
resonance imaging (MRI) or computed tomography (CT) scan, per International Working Group (IWG) 
criteria.9
3.2 Secondary Endpoints
Secondary efficacy endpoints:

Change in total symptom score (TSS) at Week 24 from baseline as measured by Myelofibrosis
Symptom Assessment Form (MFSAF) v4.0

At least 35% reduction in spleen volume from baseline (SVR35) as measured by MRI or CT scan, 
per IWG criteria

Duration of SVR35

Change in fatigue at Week 24 from baseline, as measured by the PROMIS Fatigue SF 7a
Page 13 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Change in physical functioning at Week 24 from baseline, as measured by the physical 
functioning domain of the European Organisation for Research and Treatment of Cancer 
(EORTC) quality of life questionnaire (QLQ)-C30

Anemia response per IWG criteria

Overall survival

Leukemia-free survival

Reduction in grade of bone marrow fibrosis from baseline as measured by the European 
consensus grading system10
3.3 Exploratory Endpoints
Exploratory endpoints:

At least 50% reduction in palpable splenomegaly from baseline per IWG criteria

Red blood cell (RBC) transfusion during study drug treatment

Change in quality of life from baseline as measured by the global health status/quality of life 
domain of the EORTC QLQ-C30

Change in the summary score for the EORTC QLQ-C30 from baseline

Progression-free survival (PFS) per IWG criteria

Change in frequency of allelic mutations from baseline

Change in EuroQol 5 Dimensions 5 Levels Health State Instrument (EQ-5D-5L) from baseline

Change in fatigue-related symptoms from baseline as assessed by the PROMIS Fatigue 7a 
symptom items

Change in impacts associated with fatigue from baseline as assessed by the PROMIS Fatigue 7a 
impact items.

Translational biomarkers and correlation with clinical outcomes.

Overall response of clinical improvement per IWG criteria 

At least 50% reduction in TSS at Week 24 from baseline (TSS50W24) 

Time to first TSS50

Duration of TSS50 

TSS response rate at any time based on meaningful change threshold (MCT) 

Time to first TSS response 

Duration of TSS response 
Page 14 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.4 Safety Endpoints
The safety endpoints will be based on the following evaluations:

Adverse event (AE) monitoring

Physical examinations

Vital sign measurements

Electrocardiogram (ECG) variables

Clinical laboratory testing (hematology and chemistry).
3.5 Pharmacokinetic Endpoints
Sparse PK samples will be collected at specified time points (see study activities table in Appendix D).  
Individual plasma concentrations of navitoclax and possible metabolite(s) from sparse PK sampling will 
be tabulated and summarized.  Population PK parameters of navitoclax such as apparent oral clearance 
(CL/F) and apparent volume of distribution (V/F) may be estimated using non-linear mixed effects 
model.
Further details regarding PK sampling are provided in the Operations Manual, Section 3.7.
3.6 Biomarker Research Endpoints
Biospecimens (whole blood, plasma, bone marrow aspirate, and/or bone marrow core) will be collected 
at specified time points (Appendix D) throughout the study to evaluate known and/or novel disease-
related or drug-related biomarkers in circulation or at tissue sites.  Some of these samples may be 
optional.  Types of biomarkers may include nucleic acids, proteins, lipids, and/or metabolites, either free 
or in association with particular cell types.  The analyses may include but are not limited to:  mutational 
status, BCL-2 family profiling, and inflammatory cytokine reduction.  This research may be exploratory in 
nature and the results may not be included with the clinical study report.
Further details regarding the biomarker research rationale and collection time points are located in 
Appendix D and the Operations Manual, Section 3.8.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3, double-blind, placebo-controlled, randomized, 2-arm study evaluating the efficacy and 
safety of the combination of navitoclax and ruxolitinib compared to ruxolitinib, in subjects with 
intermediate-2 or high-risk MF.  The target population comprises adult subjects with MF who have not 
been previously treated with JAK2 inhibitor therapy with measurable splenomegaly and are not 
candidates for allogenic-stem cell transplantation.
Page 15 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Approximately 230 subjects will be enrolled.  Subjects will be randomized in a 1:1 ratio to one of the 
following treatment arms, with stratification factors of intermediate-2 versus high risk (Dynamic 
International Prognostic Scoring System Plus [DIPSS+])11 and platelet count ≤ 200 × 109/L versus 
> 200 × 109/L:

Arm A – Experimental group:  navitoclax + ruxolitinib

Arm B – Control group:  placebo to match navitoclax + ruxolitinib
Dosing of study drugs:

Navitoclax/placebo:

Platelet count > 150 × 109/L:  200 mg once daily starting dose

Platelet count ≤ 150 × 109/L:  100 mg once daily starting dose; escalate to 200 mg once daily 
after ≥7 days, if tolerable (platelets ≥ 75 × 109/L).

After the Week 25 Day 1 visit, dose may be increased to 300 mg once daily at the discretion 
of the investigator based on platelet count for subjects with sub-optimal spleen response 
defined as failure to achieve a spleen volume reduction of at least 10%.

Ruxolitinib (administered per USPI/SmPC/local prescribing guidance):

Platelet count > 200 × 109/L:  20 mg twice daily starting dose

Platelet count 100 × 109/L to 200 × 109/L:  15 mg twice daily starting dose.

Ruxolitinib dose adjustment in subjects with hepatic or renal impairment should be 
determined per local label/prescribing guidance.
Ruxolitinib and navitoclax/placebo will be administered beginning on Day 1 at the individualized starting 
dose based on baseline platelet counts determined within 24 hours prior to the first dose.  The starting 
dose of ruxolitinib may be adjusted at the discretion of the investigator, as medically appropriate in 
consultation with the AbbVie Therapeutic Area Medical Director/Scientific Director (TA MD/SD), with 
subsequent increase in dose as described in Table 1.  Ruxolitinib and navitoclax/placebo dose reductions 
are permissible, as needed, for management of toxicities (Section 6.2).
Treatment with study drugs may continue until end of clinical benefit or occurrence of unacceptable 
toxicity or discontinuation criteria have been met.  At the end of study drug treatment, a treatment 
completion and 30-day safety visit will be conducted.
After documented disease progression or initiation of post-treatment cancer therapy, the subject will 
enter the survival follow-up phase.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual.
See Section 5 for information regarding eligibility criteria.
Page 16 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Figure 1.
Study Schema
DIPSS+ = Dynamic International Prognostic Scoring System Plus; Int = intermediate; Plt = platelet; PMF = primary myelofibrosis; 
SMF = secondary myelofibrosis
Option for Safety Lead-In Phase
The Sponsor plans to review safety data from at least 6 subjects administered navitoclax in combination 
with ruxolitinib for at least 8 weeks in either the frontline cohort of Study M16-109 or Study M16-191.  If 
the review of safety data from Study M16-109 is not completed prior to dosing the 12th subject in 
Study M16-191, enrolment will be paused to complete independent data monitoring committee (IDMC) 
review of safety data from the first 12 subjects enrolled in Study M16-191.
4.2 Discussion of Study Design
Choice of Control Group
Ruxolitinib is the current standard treatment that is approved for patients with MF and induces 
improvement in splenomegaly and disease-related symptoms compared with placebo or best available 
therapy.2  This study compares navitoclax in combination with ruxolitinib to placebo in combination with 
ruxolitinib.  The choice of control group allows for a double-blind assessment of the contribution of 
navitoclax to the safety and efficacy of the backbone treatment of ruxolitinib.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with MF.  All clinical 
and laboratory procedures in this study are standard and generally accepted.
Page 17 of 125
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Suitability of Subject Population
JAK2 inhibition induces down-regulation of the anti-apoptotic protein myeloid cell leukemia 1 (MCL-1) 
suggesting a role for navitoclax, a BCL-XL inhibitor, in the treatment of myeloproliferative neoplasms 
including MF.  Therefore, subjects diagnosed with MF (PMF or SMF) represent the target population for 
this study.
Selection of Doses in the Study
The recommended starting dose of ruxolitinib for MF is according to the approved label and is based on 
the subject's baseline platelet count determined within 24 hours prior to the first dose:  20 mg twice
daily (> 200 × 109/L) or 15 mg twice daily (100 × 109/L to 200 × 109/L).  The investigator may adjust the 
starting dose of ruxolitinib as medically appropriate after consultation with the AbbVie TA MD/SD, with 
subsequent increase in dose as shown in Table 1.
As a BCL-XL inhibitor, navitoclax causes thrombocytopenia via intravascular apoptosis of platelets.  
AbbVie internal data indicate that the effect of navitoclax on platelet reduction is exposure-related but 
may be diminished upon continued administration.  Accordingly, thrombocytopenia may occur with 
navitoclax upon exposure to sufficient navitoclax concentrations.  Additionally, thrombocytopenia and 
anemia are the primary reasons for ruxolitinib dose reductions.12
Preliminary data from Study M16-109 showed that weekly navitoclax dose escalation from 50 mg once 
daily to 300 mg once daily in combination with ruxolitinib at ≥ 10 mg, as was initially tested in 
Study M16-109, was generally safe without clinically relevant thrombocytopenia-related bleeding.  In 
Study M16-109, 83% of subjects experienced a dose reduction of navitoclax during study treatment with 
the primary reason being thrombocytopenia.  Of the subjects with navitoclax dose reductions for 
thrombocytopenia, 60% received 300 mg of navitoclax.  Therefore, doses of navitoclax < 300 mg once 
daily seem to be better tolerated in patients with MF.
In addition, a mechanistic PK/PD model was used to evaluate the effect of navitoclax and ruxolitinib on 
platelets counts.  The model incorporated different mechanisms by which navitoclax and ruxolitinib 
cause thrombocytopenia (navitoclax by peripheral platelet apoptosis and ruxolitinib by slowing platelet 
production).  Simulations were conducted at:

Different starting doses of navitoclax (100 to 300 mg once daily)

Starting at 100 mg once daily with a weekly ramp-up to 200 mg once daily
Simulations indicate that the maximum decreases in platelet count and incidences of Grade 3/4 
thrombocytopenia for the weekly ramp-up from 100 to 200 mg once daily were either similar to or 
slightly lower than those predicted at a flat starting dose of 200 mg (up to 5% difference).
The proposed starting dose of navitoclax in combination with ruxolitinib is 200 mg once daily or 100 mg 
once daily based on platelet counts determined pre-dose within 24 hours of first dose.  To minimize the 
risk of relevant thrombocytopenia, AbbVie has proposed a lower starting dose of 100 mg once daily for 
subjects with a baseline platelet count ≤ 150 × 109/L.  For subjects with a baseline platelet count of 
≤150 × 109/L, the dose of navitoclax will be increased to 200 mg once daily after approximately 7 or 
more days, provided the platelet count remains ≥ 75 × 109/L.  After the Week 25 Day 1 disease 
Page 18 of 125
 

STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
assessment, navitoclax /placebo dose may be increased to 300 mg once daily at the discretion of the 
investigator based on platelet count for subjects with sub-optimal spleen response defined as failure to 
achieve a spleen volume reduction of at least 10%.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must voluntarily sign and date an informed consent (or their legally authorized 
representative can sign and date the informed consent upon subject's understanding of the 
consent, if permitted by local regulations), approved by an independent ethics committee 
(IEC)/institutional review board (IRB) prior to the initiation of any screening or study-specific 
procedures.
Demographic and Laboratory Assessments
2. Subjects ≥ 18 years of age.
3. Subject must be able to complete the MFSAF v4.0 on at least 4 out of the 7 days immediately 
preceding the date of randomization.

Subject has at least 2 symptoms with a score ≥ 3 or a total score of ≥ 12, as measured by the 
MFSAF v4.0.
4. Subject must meet the following laboratory criteria per local laboratory reference range at 
Screening:

Adequate bone marrow reserve; in the absence of growth factors, thrombopoietic factors, 
or platelet transfusions for at least 14 days prior to Week 1 Day 1.

Platelet count ≥ 100 × 109/L

Absolute neutrophil count (ANC) ≥ 1 × 109/L.

Renal function:  calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault 
formula.

Hepatic function and enzymes:

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × upper limit 
of normal (ULN)

Total bilirubin ≤ 1.5 × ULN (exception:  subjects with Gilbert's Syndrome may have total 
bilirubin > 1.5 × ULN)

Coagulation:  activated partial thromboplastin time (aPTT) and prothrombin time (PT) or 
international normalized ratio (INR) ≤ 1.5 × ULN.
Page 19 of 125

STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5. Subject is willing and able to comply with procedures required in this protocol.
Disease Activity
6. Subject with a documented diagnosis of PMF as defined by the World Health Organization 
classification11 or SMF (post polycythemia vera [PPV]-MF or post essential thrombocythemia 
[PET] – MF).
7. Subject classified as intermediate-2 or high-risk MF as defined by the DIPSS+ (Appendix F).13
8. Subject must not have received prior treatment with a JAK2 inhibitor.
9. Subject must not have received prior treatment with a B-cell lymphoma 2 homology 3 (BH3) 
mimetic compound or bromodomain and extra-terminal motif (BET) inhibitor or allogeneic stem 
cell transplant.
10. Subject has splenomegaly defined as spleen palpation measurement ≥ 5 cm below costal 
margin or spleen volume ≥ 450 cm3 as assessed centrally by MRI or CT scan.
11. Subject must be ineligible for stem cell transplantation at time of study entry due to age, 
comorbidities, or unfit for unrelated or unmatched donor transplant and other criteria per 
National Comprehensive Cancer Network guidelines.14
12. Subject must not have received splenic irradiation within 6 months prior to the Screening 
Visit or had a prior splenectomy.
13. Subject must not have leukemic transformation, defined as > 10% blasts in peripheral blood 
or bone marrow.
14. Subject with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 
or 2.
Subject History
15. Subject must not have cardiovascular, endocrinologic, hepatic, immunologic, metabolic, 
neurologic, psychiatric, pulmonary, renal disease, or any other condition that, in the opinion of 
the investigator, could adversely affect the subject's participation in this study (including the 
capacity to provide consent) or the interpretation of study results.
16. Subject must not have history of an active malignancy other than MF within 2 years prior to 
Screening, except for:

Adequately treated in-situ carcinoma of the cervix

Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin

Asymptomatic prostate cancer without known metastatic disease and with no requirement 
for therapy

Adequately treated in-situ carcinoma of esophagus or gastric mucosa.
17. Subject must not have known human immunodeficiency virus (HIV) infection.  Note:  HIV 
testing does not need to be conducted at Screening unless it is required per local guidelines or 
institutional standards.
Page 20 of 125

STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
18. Subject must not have known hepatitis B (HBV) or hepatitis C (HCV) infection requiring 
treatment.  Subjects with an undetectable viral load within 3 months of Screening and those 
with serologic evidence of prior vaccination to HBV (i.e., HBs antigen [Ag-], and anti-HBs+) may 
participate.  (Hepatitis B or C testing is not required at Screening unless it is required per local 
guidelines or institutional standards).
19. Subject must have a negative tuberculin skin test (purified protein derivative, PPD) and/or 
interferon-gamma release assay (IGRA), or any approved test per local guidelines, or have no 
evidence of latent tuberculosis (TB) prior to enrollment.
20. Subject must not have any clinically significant, uncontrolled medical conditions including, 
but not limited to:

Ongoing systemic infection (viral, bacterial, mycobacterial, or fungal)

Febrile neutropenia.
21. No history of an allergic reaction or significant sensitivity to constituents of the study drug 
(and its excipients) and/or other products in the same class.
22. No clinically relevant or significant ECG abnormalities, including ECG with QT interval 
corrected for heart rate (QTc) using Fridericia's formula (QTcF) > 450 msec (males) or 
> 470 msec (females).
23. No known active SARS-CoV-2 infection.  Subjects must not have signs/symptoms associated 
with SARS-COV-2 infection or known exposure to a confirmed case of SARS-CoV-2 infection 
during the 14 days prior to Screening.
Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may 
only rescreen after they meet the following SARS-CoV-2 viral clearance criteria:

Symptomatic subjects:  At least 2 consecutive negative viral tests ≥ 24 hours apart 
conducted at least 10 days after resolution of symptoms, defined as resolution of fever 
without use of antipyretics and improvement in respiratory symptoms (e.g., cough, 
shortness of breath).

Asymptomatic subjects (if acceptable locally):  At least 2 consecutive negative viral tests 
≥24 hours apart conducted at least 10 days after the prior positive result (Note:  subjects 
who develop symptoms will follow guidance above for symptomatic subjects).
Frequency or timing of SARS-CoV-2 testing and the interval between testing for the above viral 
clearance criteria may be adjusted to account for epidemiological trends, updated information 
regarding infectivity, and local/institutional guidelines.
Contraception
24. For all females of child-bearing potential; a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at baseline prior to the first dose of study drug.
25. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control, that is effective from Study Day 1 through at least 30 days after the last dose of 
study drug.  Female subjects of non-childbearing potential do not need to use birth control.
Page 21 of 125

STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
26. If female, not pregnant, breastfeeding, or considering becoming pregnant during the study 
or for approximately 30 days after the last dose of study drug.
27. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Study Day 1 through 90 days after the last dose of study drug, to practice the 
protocol-specified contraception.
28. If male not considering fathering a child or donating sperm during the study or for 
approximately 90 days after the last dose of study drug.
Concomitant Medications
29. Subject must not receive anticancer therapy for another active malignancy or MF, including 
chemotherapy, radiation therapy, hormonal therapy (with the exception of hormones for 
thyroid conditions or estrogen replacement therapy) within 30 days, or hydroxyurea or other 
supportive medication used for cytoreduction, or steroid therapy for myelofibrosis or for anti-
neoplastic intent within 7 days, prior to first dose of study drug, and during the study drug 
treatment period.
30. Subject must not receive medication that interferes with coagulation or platelet function 
within 3 days prior to the first dose of study drug or during the study drug treatment period, 
except for low dose aspirin (up to 100 mg daily) and low molecular weight heparin (LMWH).
31. Subject must not receive biologics for MF within 30 days prior to the first dose of study drug 
and during navitoclax and ruxolitinib administration.
32. Subject must not have received any live vaccine within 4 weeks prior to the first dose of 
study drug, or be expected to need of live vaccination during study participation including at 
least 4 weeks after the last dose of study drug.
33. Subject must not have been treated with any investigational drug within 30 days prior to the 
first dose of study drug, or currently be enrolled in another clinical study, or another research 
study except for observational studies with collection of demographic data.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:

Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND an FSH level > 40 IU/L.
Page 22 of 125

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy while taking study drug(s) and for 
at least 30 days after the last dose of study drug.

Females must commit to one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation initiated at 
least 30 days prior to study Baseline Day 1.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).

Practice true abstinence, defined as:  Refraining from heterosexual intercourse when 
this is in line with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable).

If required per local practices, male or female condom with or without spermicide OR cap, 
diaphragm or sponge with spermicide should be used in addition to one of the birth control 
methods listed above (excluding true abstinence).
Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
Contraception Requirements for Males
Male subjects who are sexually active with a female partner of childbearing potential, must agree to use 
condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through at 
least 90 days after the last dose of study drug:

His female partner(s) must also use at least 1 of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days 
prior to study Baseline Day 1

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to study Baseline Day 1
Page 23 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure)

intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy, and is the sole sexual partner of the trial subject)
5.3 Prohibited/Cautionary Medications and Therapy
Anti-cancer therapy for another active malignancy or MF including chemotherapy, immunotherapy, 
radiotherapy, hormonal therapy (with the exception of hormones for thyroid conditions or estrogen 
replacement therapy), and other investigational agents are not allowed during study drug treatment.  
Treatment with supportive medications for MF such as interferon, erythropoietin, danazol, and steroids, 
is not permitted during study drug treatment.  Steroid therapy for MF or for anti-neoplastic intent will 
not be allowed within 7 days prior to the first dose of study treatment or during study drug treatment.  
If medically indicated, allowed steroid therapy includes inhalational steroids for the treatment of asthma 
or chronic obstructive pulmonary disease, topical steroids, and steroids for prevention and/or treatment 
of transfusion related reactions.  Steroids for any other indications should be limited to lower dose 
and/or short duration.
Biologics for MF will not be allowed within 30 days prior to the first dose of study drug and during 
navitoclax/placebo or ruxolitinib administration.
Medication that interferes with coagulation or platelet function (e.g., warfarin, apixaban, clopidogrel, 
tirofiban, disulfiram [potential prolongation of PT]), except for low dose aspirin (up to 100 mg daily) and 
LMWH, are not allowed during study drug treatment.  Dose adjustments for LMWH should be made 
based on the subject's platelet counts and the local label of the agent being used concomitantly.
Hydroxyurea or other medications used for cytoreduction should be discontinued 7 days prior to first 
dose of study drug and are not allowed during study drug treatment.
Janus kinase inhibitors for the treatment of inflammatory diseases are not permitted during study drug 
treatment.
Treatment with NSAIDs for limited duration is permitted during study treatment if platelet counts 
>100 × 109/L.
Selective serotonin re-uptake inhibitors and serotonin and norepinephrine reuptake inhibitors (SSRIs 
and SNRIs; e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine) are 
cautionary as they may increase the risk of bleeding events.
The following concomitant medications are cautionary during study drug treatment as they may 
potentially lead to drug-drug interaction(s).  The investigator should assess whether a potential study 
subject is taking any of the medications in the categories described below and, if so, document the use 
of medications known or suspected to fall in the following medication categories:
Page 24 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Strong cytochrome P450 (CYP) 3A inhibitors (e.g., ketoconazole and clarithromycin), and foods 
that inhibit CYP3A such as grapefruit and its juice, star fruit, and Seville oranges (due to possible 
inhibition of the metabolism of navitoclax).
Ruxolitinib is predominantly metabolized by CYP3A4 and to a lesser extent by CYP2C9.  For 
subjects who are taking strong CYP3A4 inhibitors (such as ketoconazole and clarithromycin) or 
fluconazole concurrently with study drug treatment, the local, approved ruxolitinib product 
label should be referenced for ruxolitinib dose reduction, interruption, and discontinuation, or 
monitoring guidelines.

CYP2C8 substrates such as glitazones and select statins (due to expected inhibition of the 
metabolism of CYP2C8 substrates).

CYP2C9 substrates such as phenytoin and tolbutamide (due to expected inhibition of the 
metabolism of CYP2C9 substrates).

Strong CYP3A inducers such as rifampin and carbamazepine (due to possible induction of the 
metabolism of navitoclax).  The local, approved ruxolitinib product label should be referenced 
for monitoring guidelines.

P-glycoprotein (P-gp) substrates such as digoxin, and breast cancer resistance protein (BCRP) 
substrates such as rosuvastatin (due to possible inhibition of these transporters by navitoclax).

Inhibitors and inducers of P-gp and BCRP (navitoclax is a substrate of P-gp and BCRP).

The local, approved ruxolitinib product label should be referenced for monitoring guidelines 
when co-administered with CYP3A inducers or drugs transported by P-gp and BCRP.
A sample list of excluded and cautionary medications is provided in (Appendix G).  Since a complete list 
of medications that should only be used with caution cannot be provided, please refer to the 
appropriate product label and/or contact the AbbVie TA MD/SD whether a specific concomitant 
medication falls into the above-mentioned categories.  Information regarding potential drug interactions 
with navitoclax can also be located in the current navitoclax Investigator's Brochure.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of enrollment or receives during the study 
must be recorded from the time of signing the consent form at Screening until the 30 days after the last 
dose of study medication.
Best supportive care and treatment is allowed for each subject, e.g., antiemetics, antibiotics, 
transfusions, nutritional support, pain control etc, with the exception of therapy and medications 
detailed in Section 5.3.
Colony stimulating factors (G-CSF, GM-CSF) are allowed during administration of navitoclax if deemed 
necessary by the investigator and if mutually agreed upon by AbbVie TA MD/SD.
Anti-herpes and anti-pneumocystis carinii/jiroveci pneumonia (PCP) prophylaxis should be considered if 
clinically indicated.  Trimethoprim and sulfamethoxazole can be considered for PCP prophylaxis with 
Page 25 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
close clinical monitoring; whilst there is a potential for drug-drug interactions, any clinical effects are 
likely to be limited.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with navitoclax can be located in the 
navitoclax Investigator's Brochure.
Subjects must be able to safely discontinue any prohibited medications as detailed in Section 5.1.  
Subjects must be consented for the study prior to discontinuing any prohibited medications for the 
purpose of meeting study eligibility.
COVID-19 Pandemic-Related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, non-replicating viral 
vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during screening or 
the treatment period, as long as components of the vaccine are not contraindicated.  Investigators are 
to follow the prescribing information for the vaccine.
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the investigator/treating physician and the subject.
The potential impact of navitoclax and ruxolitinib on SARS-CoV-2 vaccination is unknown.  Therefore, the 
timing of administration of vaccine in relation to the study drug should be based on the investigator's 
medical assessment of the subject's disease.  These recommendations may be subject to change based 
on the evolving knowledge around the use of SARS-CoV-2 vaccines in patients with MF and as more data 
are collected in real-world scenarios and clinical trials. 
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  Refer to the 
Operations Manual for instructions on reporting any adverse events associated with the COVID-19 
vaccine.
5.5 Subject Discontinuation from Study Drug Treatment and 
Discontinuation of Study
Treatment with study drug may continue until end of clinical benefit or occurrence of unacceptable 
toxicity or discontinuation from study.  A subject may voluntarily withdraw or be withdrawn from study 
drug treatment at any time for reasons including, but not limited to, the following:

The subject is no longer deriving clinical benefit from study drug treatment, has disease 
progression, or the investigator believes it is in the best interests of the subject.

The subject requires alternative therapy for treatment of MF.

Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie TA MD.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.
Page 26 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Introduction of prohibited medications and continuation of the study drug would place the 
subject at risk.

The subject becomes pregnant while on study drug, or begins or intends breastfeeding.

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements, which would put the subject at risk for continued participation in the trial.

The subject withdraws consent to receiving study drug treatment.

Any other medical reason that AbbVie or the investigator deems appropriate.

If the study treatment is unblinded by the investigator, that subject would need to be 
discontinued from study treatment and post-treatment or survival follow-up would commence.
Withdrawal from study (including all follow-up) will occur under the following circumstances:

Withdrawal of consent for follow-up (this request must be documented in the subject's medical 
records and signed by the investigator)

Lost to follow-up

Death of subject

Study termination by Sponsor.
Discussion with the TA MD/SD is recommended prior to discontinuation of a subject from study 
treatment for any reason other than described above to ensure all acceptable mitigation steps have 
been evaluated.
Subjects with disease progression or relapse may continue to receive study treatment if the investigator 
considers it to be in the best interest of the subject. Disease assessment per protocol criteria at the time 
of disease progression will be captured in EDC. The subject will be monitored per study procedures 
described in Appendix D. Activity Schedule or more often if the investigator considers it necessary.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  This study will be 
monitored regularly by AbbVie in addition to an independent data monitoring committee (IDMC).  The 
study has a safety review plan to assess laboratory and adverse event data on a weekly basis and serious 
adverse events on a daily basis.  An aggregate review of the blinded aggregated data will be conducted 
once every 3 months.  The product safety team including cross functional members is responsible for 
the ongoing safety monitoring of the program, including recommendations to modify or discontinue the 
study for unanticipated safety events.  The study may be terminated due to unfavorable risk benefit 
assessment or at the IDMC's recommendation based on safety or efficacy concerns.  The investigator 
may also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator; the investigator must promptly notify any 
subjects enrolled in the study and arrange alternative therapy for MF.
Page 27 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual (Appendix I).
The investigator should contact the AbbVie TA MD/SD before discontinuing a subject from the study for 
a reason other than "planned per protocol" to ensure that all acceptable mitigation steps have been 
explored.
Refer to the Operations Manual (Appendix I) for details of how to handle activities/procedures.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
During the study drug dosing period, if a subject has a confirmed (viral test positive or symptomatic 
disease) or is suspected to have COVID-19, recommend study drug or placebo interruption until 
infection is considered resolved per local requirements/recommendations, based on either clinical 
course or laboratory SARS-CoV-2 testing results.  If the investigator feels interrupting study drug or 
placebo during active COVID-19 infection is not in the subject's best interest, navitoclax or placebo 
dosing may be continued without interruption, in which case the TA MD/SD should be notified within 48 
hours after this decision.
Ruxolitinib dosing may continue without changes or may be adjusted or interrupted, as determined by 
the investigator on a case-by-case basis, based on overall benefit/risk assessment including potential 
effects of reduced treatment intensity on underlying MF and/or risk of COVID-19-related sequelae.  
COVID-19 and MF treatment regimens should be assessed for drug-drug interactions and potential need 
for dose adjustments.  Ruxolitinib dosing may be tapered when needed to avoid exacerbation of disease 
associated with abrupt interruption.
Per protocol, the investigator can temporarily interrupt study drug at any time for a safety issue, or for 
any reason if they feel that the risk outweighs the benefit of study treatment.  Treatment interruption 
longer than 28 days must be discussed with the TA MD/SD.
Subjects should be reminded by the site staff to notify the investigator immediately if they develop any 
signs and symptoms of COVID-19 infection (e.g., fever, sweating, chills, feeling tired, cough, or shortness 
of breath).
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
To minimize missing data for efficacy and safety assessments, subjects should be advised on the 
continued scientific importance of their data even if they discontinue treatment with study drug early.  
Subjects who discontinue study drug treatment should continue on study with all assessments 
conducted through post-treatment follow-up visits and survival follow up (per the Operations Manual, 
Section 2.2) until death, subject withdrawal from study participation (i.e., withdrawal of informed 
consent) or study termination, whichever occurs first.
Page 28 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
If a subject withdraws from study follow up or withdraws permission for the collection of their personal 
data, the study staff may still use available public records to obtain information about survival status 
only, as appropriate per local regulations.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed the subject has 
withdrawn and no longer wishes biomarker samples research to continue, samples will not be analyzed, 
and no new biomarker analysis data will be collected for the withdrawn subject or added to the existing 
data or database(s).  A subject may withdraw consent for optional biomarker research at any time and 
remain in the clinical study.  Data generated from clinical study and/or optional biomarker research 
before subject withdrawal of consent, will remain part of the study results.
5.7 Post-Treatment Follow Up
All subjects who discontinue study drug treatment after 24 weeks for reasons other than disease 
progression will return for post-treatment follow-up visits approximately every 12 weeks following the 
treatment completion visit to assess disease status until documented disease progression or leukemic 
transformation or initiation of post-treatment cancer therapy.
For subjects who discontinue study treatment prior to completing 24 weeks of study treatment without 
intervening new treatment for myelofibrosis and who do not have documented disease progression, 
disease response assessments, including MRI/CT scans, should be conducted per the visit schedule up to 
and including the Week 25 Day 1 visit.  Once the Week 25 Day 1 disease response assessments are 
completed the subject will continue on study every 12 weeks in post-treatment follow up, or every 
2 months in survival follow up, based on post-treatment status (i.e., subjects who achieve disease 
progression, have lost clinical benefit, or have started another treatment would move onto survival 
follow up).
5.8 Survival Follow Up
For all subjects, survival follow-up will be performed approximately every 2 months for up to 8 years 
after the last subject last dose (unless informed consent has been withdrawn for collection of such 
information; this request must be documented in the subject's source documentation and electronic 
case report form [eCRF]), or more frequently, as requested by the Sponsor to support data analyses.  
Survival information (date and cause of death, details of post-treatment cancer therapies including 
response and progression) may be collected via telephone calls (e.g., to subject or family member), clinic 
visits, and/or public database searches.  If the subject withdraws from survival follow up, the study staff 
may use public information sources (e.g., public records, death certificates) to obtain information about 
survival status only, as appropriate per local regulations.
5.9 Study Drug
Navitoclax and matching placebo will be provided by the Sponsor as film-coated tablets (25 mg and 
100 mg) for oral administration taken once daily in the morning.  Tablets must be taken with water 
within approximately 30 minutes after the completion of a meal.  Tablets must be swallowed whole and 
Page 29 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
must not be broken, chewed, or crushed.  If the subject misses a dose of navitoclax/placebo, the missed 
dose should be taken with food and water within 8 hours of the scheduled dose time.  After 8 hours, the 
missed dose should not be taken and the next dose of navitoclax/placebo will be at the next scheduled 
dosing time.
If the subject vomits following dosing, no additional dose should be taken that day.  The next prescribed 
dose of navitoclax/placebo should be taken at the usual time the following day.
Ruxolitinib tablets will be provided by AbbVie or sourced locally by the sites, depending on country 
regulations.  Ruxolitinib should be taken orally twice daily at approximately the same time each day, 
once in the morning (at the same time as navitoclax, if applicable) and once in the evening, 
approximately 12 hours later.  The absorption of ruxolitinib is not affected by food and ruxolitinib may
be taken with or without food.  If the subject misses a dose of ruxolitinib, the subject should take the 
next dose at the scheduled time.  The subject should not take 2 doses at the same time.
Each kit will be labeled per local requirements and this label must remain affixed to the kit.  Upon 
receipt, study drug should be stored as specified on the label and kept in a secure location.  Each kit will 
contain a unique kit number.  This kit number is assigned to a subject via interactive response 
technology (IRT) and encodes the appropriate study drug to be dispensed at the subject's corresponding 
study visit.  Site staff will complete all blank spaces on the label before dispensing to subjects.  Study 
drug will only be used for the conduct of this study.
If a subject is unable to come to the study site to pick up their study drug due to COVID-19, a direct-to-
patient (DTP) study drug shipment can be made from the study site to the subject if allowed by local 
regulations.  AbbVie will submit any required notifications to the regulatory authority as applicable.  
Refer to the Operations Manual in Appendix I for details on DTP shipment of study drug.
Subjects will record the time of navitoclax/placebo dosing on a subject dosing diary for the 2 doses prior 
to the Week 2 Day 1, Week 3 Day 1, and Week 5 Day 1 visits.  Subjects will be instructed to return all 
drug containers (even if empty) to the study site personnel at each study visit.  Study site personnel will 
document the containers and number of tablets returned.
Upon completion of or discontinuation from study treatment, all original study drug units (containing 
unused study drugs) will be returned to the sponsor (or designee) or destroyed on site.  All return or 
destruction procedures will be according to instructions from the sponsor and according to local 
regulations following completion of drug/device accountability procedures.
Further information on study drug, packaging, labeling, etc., is provided in the Operation Manual, 
Section 6.
5.10 Randomization/Drug Assignment
Interactive Response Technology (IRT) will be utilized to register (screen and randomize) subjects on 
study.  The site will contact the IRT to obtain a screening (subject) number only after the subject has 
signed the informed consent and prior to any study-specific procedures being performed (e.g., labs are 
drawn).  Subjects who satisfy all eligibility criteria at Screening will proceed to being randomized based 
Page 30 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
on baseline platelet counts determined within 24 hours prior to the first dose.  The site will contact the 
IRT to complete the randomization process and obtain study drug assignment.
The IRT will randomize subjects into 2 treatment arms using 1:1 randomization ratio.  Randomization 
will be stratified by:

Intermediate-2 versus high risk (DIPSS+)

Platelet count ≤ 200 × 109/L versus > 200 × 109/L (determined within 24 hours prior to first dose)
Blinding of Investigational Product
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment throughout the study.  To maintain the blind, the 
navitoclax film-coated tablets and placebo-film-coated tablets provided for the study will be identical in 
appearance.
The IRT will provide access to unblinded subject treatment information in the case of a medical 
emergency.  AbbVie must then be notified within 24 hours of the blind being broken.  The date and 
reason that the blind was broken must be recorded in the source documentation and electronic case 
report form (eCRF), as applicable.
5.11 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying independent ethics committee (IEC)/independent review 
board (IRB), regulatory authorities (as applicable), and AbbVie.
5.12 Data Monitoring Committee
An IDMC will regularly review unblinded safety data from the ongoing study, once every 6 months, 
according to the schedule provided in the IDMC charter, including adverse events and laboratory results.  
The unblinded safety analyses will be performed by an independent statistical data analysis center 
(SDAC) external to AbbVie and reviewed by the IDMC.  AbbVie personnel will remain blinded and will 
not have access to the unblinded analyses prepared for the IDMC.  The IDMC will provide 
recommendations to AbbVie as per the IDMC charter including any modifications to the protocol or 
discontinuations of the study.
A separate IDMC charter will be prepared outside of the protocol that will further describe the IDMC 
membership (which will include individuals with experience in treatment of patients with 
myeloproliferative neoplasms), roles and responsibilities of the IDMC members, frequency and scope of 
the data reviews, and expectations for blinded communications.
Page 31 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An adverse event is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not the event is considered causally related to the 
use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations," such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an adverse event or not.  Any worsening of a pre-existing condition or 
illness is considered an adverse event.  Worsening of disease under study or underlying cancer (serious 
or nonserious event) should be collected as an adverse event due to disease progression on the eCRF.  
Worsening in severity of a reported adverse event should be reported as a new adverse event.  
Laboratory abnormalities and changes in vital signs are considered to be adverse events only if they 
result in discontinuation from the study, necessitate therapeutic medical intervention, meets protocol 
specific criteria (see Section 6.2 regarding toxicity management), and/or if the investigator considers 
them to be adverse events.
Page 32 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study.  All adverse events will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an adverse 
event if the surgery/procedure is being performed for a pre-existing condition and/or the 
surgery/procedure has been pre-planned prior to study entry.  However, if the pre-existing condition 
deteriorates unexpectedly during the study (e.g., surgery performed earlier than planned), then the 
deterioration of the condition for which the elective surgery/procedure is being done will be considered 
an adverse event.  Hospitalization for the purpose of monitoring platelet counts post study drug 
administration is not considered an adverse event or serious adverse event.  If the hospitalization is 
prolonged due to an event not related to monitoring platelet counts, then adverse event/serious 
adverse event criteria is to be assessed.
If an adverse event, whether associated with study drug or not, meets any of the following criteria, it is 
to be reported to AbbVie clinical pharmacovigilance as a serious adverse event within 24 hours of the 
site being made aware of the serious adverse event (refer to Section 4.2 of the Operations Manual for 
reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have resulted 
in immediate fatality if medical intervention had not been taken.  This 
does not include an event that would have been fatal if it had 
occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length of 
time or prolongs the subject's hospital stay.  This does not include an 
emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Page 33 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes listed 
above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important medical 
event.  Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug 
abuse.
All adverse events reported from the time of study drug administration until 30 days after the last 
dose/discontinuation of study drug administration will be collected, whether solicited or spontaneously 
reported by the subject.  In addition, study procedure-related serious and nonserious adverse events 
will be collected from the time the subject signs the study-specific informed consent.
The following definitions will be used for serious adverse reactions (SARs) and suspected unexpected 
serious adverse reactions (SUSARs):
SAR
Defined as all noxious and unintended responses to an Investigational 
Medicinal Product (IMP) related to any dose administered that result 
in death, are life-threatening, require inpatient hospitalization or 
prolongation of existing hospitalization, result in persistent or 
significant disability or incapacity, or are a congenital anomaly or 
birth defect.
SUSAR
A suspected SAR:  refers to individual serious adverse event (SAE) 
case reports from clinical trials where a causal relationship between 
the SAE and the IMP was suspected by either the Sponsor or the 
investigator, is not listed is the applicable Reference Safety 
Information (RSI), and meets one of the following serious criteria:  
results in death, is life-threatening, requires hospitalization or 
prolongation of an existing hospitalization, results in persistent or 
significant disability or incapacity, or is a congenital anomaly or birth 
defect.  All individually reported SARs are considered suspected.
AbbVie will be responsible for SUSAR reporting for the investigational medicinal product (IMP) in 
accordance with global and local regulatory requirements in participating countries.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Page 34 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Adverse Event Severity and Relationship to Study Drug
The investigator will rate the severity of each adverse event according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.  If a reported adverse event 
increases in severity, the initial adverse event should be given an end date and a new adverse event 
must be reported with a different onset date than the end date of the previous adverse event to reflect 
the change in severity.  The dates of the adverse events cannot overlap.
For adverse events not captured by the NCI CTCAE, the following criteria should be used:
Grade 1
Mild; asymptomatic or mild symptoms; clinical diagnostic observations only; 
intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self- care activities of daily living.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
For all reported serious adverse events that increase in severity, the supplemental eCRFs also need to be 
updated to reflect any changes due to the increase in severity.  For serious adverse events considered as 
having "no reasonable possibility" of being associated with study drug, the investigator will provide an 
"other" cause of the event.
The investigator will use the following definitions to assess the relationship of an adverse event to the 
use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
The investigator will assess the relationship of each adverse event to navitoclax and, if applicable, to 
ruxolitinib.  For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no reasonable 
possibility of being related to study drug will be considered "not associated."  In addition, when the 
investigator has not reported causality or deemed it not assessable, AbbVie will consider the event 
associated.
Page 35 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie within 24 hours 
after the site becomes aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.5).  If a pregnancy occurs in a study subject or in the partner of a study 
subject, information regarding the pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained prior to collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partners will be collected from the 
date of the first dose through 30 days following the last dose of study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
6.2 Toxicity Management
All subjects should be monitored according to the Activity Schedule in Appendix D for new-onset 
non-hematologic toxicity and renal toxicities, with dose delay or reduction as appropriate.
Navitoclax/Placebo
Navitoclax may be associated with cytopenias, notably thrombocytopenia, based on observations made 
of subjects during previous clinical trials in other indications and in the ongoing Study M16-109.
The guidelines noted below should be implemented for appropriate dosing and management of all 
subjects for safety.  If additional dose reductions or modifications that are thought to be necessary by 
the investigator, a discussion with the AbbVie TA MD/SD is required.

If a navitoclax/placebo interruption is necessary, navitoclax/placebo may be reintroduced at the 
same or lower dose based on the guidance below and in Table 1.

Current dose level 200 mg once daily; reduce to 100 mg once daily, then 50 mg once daily

Current dose; 100 mg once daily; reduce to 50 mg once daily.

The same navitoclax/placebo dose level shall not be attempted more than twice consecutively 
without prior approval from the AbbVie TA MD/SD.

Intermediate dose levels of navitoclax/placebo (e.g., 150 mg once daily) may be administered 
for moderate dose adjustments.
Ruxolitinib
For ruxolitinib, in addition to the dose modification guidelines provided below and in Table 1, the local, 
approved product label should be referenced for drug-drug interactions, precautions, monitoring, and 
dose adjustment guidelines for subjects with hepatic or renal impairment and all hematological and 
non-hematological toxicities.
Page 36 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
For subjects who require interruption of ruxolitinib per the label but are considered to be at increased 
risk for exacerbation of splenomegaly and significant symptoms, ruxolitinib dose can be tapered by the 
Investigator in consultation with the AbbVie TA MD/SD followed by interruption.
Decisions regarding continued dosing, including the navitoclax/placebo or ruxolitinib dose level to be 
administered, for individual subjects will be medically managed by the investigator and consultation 
with the AbbVie TA MD/SD is recommended.  Dosing interruptions greater than 28 days or additional 
dose modifications must be discussed with the AbbVie TA MD/SD.
Management of Thrombocytopenia and Bleeding Events
Navitoclax accelerates apoptosis of circulating mature platelets whether endogenous or transfused.  
This mechanism of toxicity differs from the thrombocytopenia caused by ruxolitinib and other 
conventional chemotherapy (i.e., toxicity to platelet progenitors in the bone marrow) and should, 
therefore, be managed according to the guidelines provided in Table 1, unless previously discussed and 
approved with the AbbVie TA MD/SD.
Hematology samples must be collected within 24 hours prior to the first dose of study drug to 
determine dose of study drug, at 4 hours after the first dose of study treatment, and on Day 2 (see 
Activity Schedule, Appendix D, and Operations Manual, Section 3.14).  The investigator should consider 
additional hematology labs on Day 3 and/or Day 4 for subjects with a lower baseline platelet count and 
for subjects who experience a > 40% decrease in platelet count on Day 2 from the pre-dose platelet 
count.  Additional hematology labs may be performed based on platelet counts as medically indicated at 
the investigator's discretion.
Any Grade ≥ 2 bleeding event (regardless of platelet count) will require interruption of dosing.  Upon 
resolution of a Grade ≥ 2 bleeding event, study drug treatment may be reintroduced at the same or 
lower dose level (in consultation with the AbbVie TA MD/SD), provided the patient is asymptomatic with 
no evidence of an active bleeding.
If platelet transfusions are required in response to active bleeding, navitoclax/placebo dosing should be 
interrupted.  It should be noted that platelet response with transfusions may not follow typical platelet 
kinetics of thrombocytopenia as with typical chemotherapy-induced thrombocytopenia.  Procedures 
consistent with local institutional blood banking guidelines regarding platelet transfusions should be 
followed.
Platelet Transfusion Recommendations:
If platelet transfusion is deemed necessary, the treating physician should be aware that due to the rapid 
apoptotic effect of navitoclax on mature platelets, the increase in platelet counts post-transfusion may 
be lower and the duration of response may be shorter.  Therefore, donor platelets collected as recently 
as possible prior to transfusion should be used.  Additional transfusions may be necessary to achieve the 
desired platelet count.  Post-transfusion platelet count monitoring should include:

A platelet count obtained 10 to 60 minutes post transfusion.

A platelet count obtained approximately 24 hours (± 1 hour) post transfusion.
Page 37 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Management of Neutropenia
There is a potential for clinically significant neutropenia given the toxicity profiles of both ruxolitinib and 
navitoclax.  The management of neutropenia guidelines, as listed in Table 1 and below, should be 
implemented for all subjects unless previously discussed and approved with the AbbVie TA MD/SD.

For Grade 3 neutropenia in addition to interruption as listed in Table 1, support with G-CSF 
and/or prophylaxis with antibiotics may be considered at the discretion of the investigator.

For Grade 4 neutropenia in addition to interruption as listed in Table 1, support with G-CSF 
and/or prophylaxis with antibiotics may be considered at the discretion of the Investigator.  If, in 
the opinion of the investigator, ruxolitinib dose can be resumed prior to recovery of ANC 
≥1.0 × 109/L or needs a dose reduction, consultation with the AbbVie TA MD/SD is necessary.
At any time during the study, if the subject presents with febrile neutropenia, navitoclax/placebo and 
ruxolitinib, if applicable, should be interrupted until resolution of the fever or infection.
Page 38 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 1.
Dose Adjustment Guidelines for Thrombocytopenia and Neutropenia

After navitoclax/placebo and/or ruxolitinib dose modification, platelet counts should be rechecked approximately 7 days or sooner as clinically 
applicable until at least 2 consecutive laboratory values indicate stable platelet count.

If treatment is interrupted for platelet count < 50 x 109/L, recheck platelets approximately every 2 to 3 days until recovery of platelets to ≥ 50 × 109/L.

Navitoclax/Placebo Dose levels for daily dosing: 200 mg, 150 mg, 100 mg, 75 mg, or 50 mg.
Hematology Results
Navitoclax/Placebo
Ruxolitinib per approved local label
Dose Modification for Thrombocytopenia
Platelet counts ≥125 x 109/L

Maintain dose if current navitoclax/placebo dose is 
200 mg QD.

Increase dose by one dose level if current 
navitoclax/placebo dose is ≤ 150 mg QD and has been 
administered for at least 7 days without any dose 
modification or interruption.

Increase dose to the label recommended 
dose for subjects who received lower 
starting dose of ruxolitinib than the label 
recommended dose if platelet counts are 
stable and current dose of ruxolitinib has 
been administered for at least 7 days 
without any dose modification or 
interruption.
Platelet counts ≥100 x 109/L to 
< 125 x 109/L

Maintain dose if current navitoclax/placebo dose is 
≥150 mg QD.

Increase dose by one dose level if current 
navitoclax/placebo dose is ≤100 mg QD and has been 
administered for at least 7 days without any dose 
modification or interruption.

Maintain current ruxolitinib dose if receiving 
≤ 15 mg twice daily.

Reduce dose to one dose level lower twice 
daily if current ruxolitinib dose ≥20 mg twice 
daily.
Platelet counts ≥75 × 109/L to
< 100 × 109/L

Maintain dose if current navitoclax/placebo dose is 
≥150 mg QD.

Increase dose by one dose level if current 
navitoclax/placebo dose is ≤100 mg QD and has been 
administered for at least 7 days without any dose 
modification or interruption.

Maintain current ruxolitinib dose if receiving 
≤10 mg twice daily. 

Reduce dose to 10 mg twice daily if current
ruxolitinib dose ≥15 mg twice daily.
Page 39 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

After navitoclax/placebo and/or ruxolitinib dose modification, platelet counts should be rechecked approximately 7 days or sooner as clinically 
applicable until at least 2 consecutive laboratory values indicate stable platelet count.

If treatment is interrupted for platelet count < 50 x 109/L, recheck platelets approximately every 2 to 3 days until recovery of platelets to ≥ 50 × 109/L.

Navitoclax/Placebo Dose levels for daily dosing: 200 mg, 150 mg, 100 mg, 75 mg, or 50 mg.
Hematology Results
Navitoclax/Placebo
Ruxolitinib per approved local label
Platelet counts ≥50 × 109/L to < 75 × 109/L

Reduce dose to one dose level lower.

Maintain dose if current navitoclax/placebo dose is 
50 mg QD and counts are stable and no risk for
bleeding per investigator discretion.

Interrupt dosing if current navitoclax/placebo dose is 
50 mg QD and platelet counts are not stable and 
there is a risk for bleeding.

Reduce dose to 5 mg twice daily. 
Platelet counts < 50 × 109/L

Interrupt dosing and resume at one dose level lower 
than prior to interruption once platelet counts 
recover to ≥50 × 109/L.

Interrupt per local label.  May taper if high 
risk for exacerbation in discussion with TA 
MD/SD.

Resume at same or lower dose once platelet 
counts recover ≥ 50 × 109/L.
Dose Modification for Neutropenia
Absolute neutrophil count (ANC) 
< 1.0 × 109/L to 0.5 × 109/L

Interrupt dosing and monitor hematology labs at 
least weekly until ANC ≥ 1.0 × 109/L.

Resume at one dose level lower than prior to 
interruption once ANC recover ≥ 1.0 × 109/ L.

Maintain current dose or interrupt per local 
label if at risk for infection per investigator 
discretion.
Absolute neutrophil count (ANC) 
< 0.5 × 109/L

Interrupt dosing and monitor hematology labs at 
least weekly or often as needed until ANC ≥ 1.0 × 
109/L.

Resume at one dose level lower than prior to 
interruption once ANC recover ≥ 1.0 × 109/ L.

Interrupt per local label.  May taper if high 
risk for exacerbation in discussion with TA 
MD/SD.

Resume at same or lower dose.  
Page 40 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Management of Infections
Subjects who develop clinically significant infections should have navitoclax/placebo and ruxolitinib 
interrupted and restart study drug treatment when signs or symptoms of infection have resolved.
If clinically indicated, anti-infective prophylaxis should be implemented at the investigator's discretion, 
including appropriate prophylaxis for viral, fungal, bacterial, or Pneumocystis jiroveci pneumonia 
infections with close monitoring as there is a potential for drug-drug interactions.
Management of Other Toxicities
For non-hematologic events, the investigator may interrupt and/or modify dosing of either of the study 
drugs, as clinically indicated.  Consultation with AbbVie TA MD/SD prior to interruption or dose 
modification is recommended.
Grade ≥ 3 gastrointestinal toxicity of nausea, vomiting, and diarrhea when additional supportive care 
fails, increase in AST, ALT, and bilirubin (Grade determined from baseline value per CTCAE criteria) that 
might be attributed to navitoclax or ruxolitinib will require interruption and possible discontinuation of 
dosing if no improvement.  Study drug treatment may be reintroduced at the same or lower dose level 
(in consultation with the AbbVie TA MD/SD) if the laboratory results or symptoms return to Grade ≤ 1 or 
to baseline at study entry.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and key secondary analyses.  
Complete and specific details of the statistical analysis will be described in the Statistical Analysis Plan 
(SAP).
The primary analysis will be performed after all ongoing, randomized subjects have completed at least 
24 weeks of disease assessment or all subjects discontinue the study, whichever occurs first.
All statistical tests will be performed at two-sided significance level 0.05 unless otherwise specified.
7.2 Definition for Analysis Populations
The intent-to treat (ITT) population includes all randomized subjects in the study.  Data from the ITT 
population will be analyzed by the treatment arm (Arm A:  navitoclax + ruxolitinib, and Arm B:  placebo + 
ruxolitinib) assigned at the time of randomization, regardless of the study drug treatment actually 
received.  The ITT population will be used for analyses of all efficacy and baseline characteristics.
The safety population consists of all subjects who received at least 1 dose of study drug.  The safety 
population will be used for all safety analyses.
Page 41 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.3 Statistical Analyses for Efficacy
Primary Efficacy Analysis
Analysis of the primary endpoint SVR35W24 will be conducted by comparing the SVR35W24 rate (the 
proportion of subjects achieving SVR35 at Week 24), using the stratified Cochran-Mantel-Haenszel (CMH) 
test.  The study is designed to test the null hypothesis:
H0:SVR35W24 rate in Arm A (navitoclax + ruxolitinib) = SVR35W24 rate in Arm B (placebo + ruxolitinib) against 
the alternative hypothesis H1:SVR35W24 rate in Arm A ≠ SVR35W24 rate in Arm B.
The stratification factors for the stratified statistical analyses will be described in detail in the SAP.
The 95% confidence interval (CI) for SVR35W24 rate will be estimated for each treatment arm based on the 
exact binomial distribution.  Subjects without spleen volume assessment at baseline or the Week 24 
timepoint will be treated as non-responders.  Details of this analysis will be provided in the SAP.
Secondary Efficacy Analyses
The following secondary endpoints will be analyzed:

Response rate endpoints:  SVR35, anemia response, reduction in grade of bone marrow fibrosis 
from baseline as measured by the European consensus grading system

Continuous endpoints: Change in TSS at Week 24 from baseline, as measured by MFSAF v4.0; 
change in fatigue at Week 24 from baseline, as measured by the PROMIS Fatigue SF 7a; change 
in physical functioning at Week 24 from baseline, as measured by EORTC QLQ-C30 v3.0

Time to event endpoints:  Duration of SVR35, OS, and LFS
Change in TSS at Week 24 from baseline is defined as the change in total symptom score at Week 24 
from baseline, as measured by MFSAF v4.0.
SVR35 rate is defined as the proportion of subjects who achieve at least 35% reduction in spleen volume 
from baseline (SVR35) at any time during the study.
Duration of SVR35 is defined as time from the first achievement of SVR35 to the first assessment where 
the spleen volume is less than 35% reduction from baseline and is at least 25% increase from the nadir 
(the lowest spleen volume).
Change in fatigue at Week 24 from baseline is defined as the change in fatigue score at Week 24 from 
baseline, measured by PROMIS Cancer Fatigue SF 7a.
Change in physical functioning at Week 24 from baseline is defined as the change in physical functioning 
score at Week 24 from baseline, as measured by EORTC QLQ-C30.
Anemia response rate is defined as the proportion of subjects who achieve anemia response at any time 
during the study.
Overall survival is defined as time from randomization to death from any cause.
Page 42 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Leukemia-free survival is defined as time from randomization to leukemic transformation (≥ 20% blasts) 
by bone marrow blasts or peripheral blood blasts per IWG criteria, or death from any cause, whichever 
occurs earlier.
Rate of reduction in grade of bone marrow fibrosis is defined as the proportion of subjects who achieve 
reduction of at least 1 grade in bone marrow fibrosis measured by the European consensus grading 
system.
Unless otherwise specified, all response rate secondary endpoints will be analyzed using the stratified 
CMH test.  The point estimate and 95% CIs based on the exact binomial distribution will be presented 
for each treatment arm.  Unless otherwise specified, subjects with missing data for a visit will be treated 
as non-responders for that visit.
Unless otherwise specified, all time to event secondary endpoints will be analyzed by using stratified 
log-rank test. Subjects who do not experience the event of interest will be censored at the last 
adequate assessment.  The hazard ratio (HR) for treatment effect and the corresponding 95% CI will be 
estimated using stratified Cox proportional hazards model.  In addition, survivorship functions will be 
estimated by using Kaplan-Meier product-limit method.  Estimated survival curves will be presented.
Unless otherwise specified, all continuous patient-reported outcome endpoints will be analyzed using 
the linear mixed effects model.  Subjects with missing data will be handled by the missing at random 
assumption within the framework of the linear mixed effects model.
Statistical analyses of secondary endpoints will be described in detail in the SAP.
Additional Efficacy Analyses
Details of additional efficacy analyses will be provided in the SAP.  Additional supportive efficacy 
statistical analyses may be performed if deemed necessary and helpful in understanding the drug effect.
Subgroup Analysis for Efficacy
Supportive subgroup analyses, such as platelet count and DIPSS+, will be performed for the primary 
endpoint.  Details of subgroup analyses will be provided in the SAP.
7.4 Statistical Analyses for Safety
Safety analyses will be performed using the safety population.
Details of the safety analyses will be provided in the SAP.
7.5 Interim Analysis
There is no plan for any interim efficacy analysis.  However, an IDMC will review unblinded safety data 
from the ongoing study (see Section 5.12).  The primary responsibility of the IDMC will be to protect the 
safety of the subjects participating in this study and make the necessary recommendations.
Page 43 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.6 Overall Type I Error Control
Overall type I error rate will be controlled for multiplicity for the primary and selected secondary 
efficacy endpoints.  Hierarchical/sequential testing approach will be used to control the overall type I 
error rate at two-sided 0.05 significance level.
The key secondary efficacy endpoints are ranked as follows:  1.  Change in TSS at Week 24 from baseline; 
2.  SVR35; 3. Anemia response; 4.  Reduction in grade of bone marrow fibrosis from baseline; 5.  OS; 6.  
LFS; 7. Change in fatigue at Week 24 from baseline; 8. Change in physical functioning at Week 24 from 
baseline.
For endpoints to be analyzed more than once (such as OS and LFS), the Lan-DeMets alpha-spending
function with O'Brien-Fleming boundary will be used to determine the efficacy boundaries for planned 
analyses.  Additional details will be provided in SAP.
7.7 Sample Size Determination
Approximately 230 subjects will be enrolled using a 1:1 randomization ratio to Arm A and Arm B by the 
stratification factors (DIPSS+:  intermediate-2 versus high risk, and platelet count:  ≤ 200 × 109/L versus 
> 200 × 109/L).  The null hypothesis H0 will be tested against the alternative hypothesis H1 using the 
stratified CMH test with two-sided significance level 0.05.
Based on published results, the SVR35W24 rate in the control arm (Arm B) is expected to be approximately 
40%.15  True improvement in SVR35W24 from 40% to 
 is considered clinically meaningful.
This study with 230 subjects will have approximately 90% power if the true SVR35W24 rates in the control 
(placebo + ruxolitinib) and treatment (navitoclax + ruxolitinib) arms are 40% and 
, respectively.
With a total of 230 subjects, the study will also have approximately 
 power to detect a statistically 
significant OS improvement in the navitoclax + ruxolitinib treatment arm, assuming a true hazard ratio 
of 
.  A total of two OS analyses are planned:  the first will be performed at the time of approximately 
70% OS information (or 
 death events); the final OS Analysis will be performed when a total of 
 
death events (100% OS information) have been observed.  The Lan-DeMets alpha-spending function 
with O'Brien-Fleming boundary will be used to determine the efficacy boundaries for these planned OS 
analyses.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
Page 44 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
applicable regulations, and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the investigator are specified in 
Appendix B.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, conflict/combat) 
occurs leading to difficulties in performing protocol-specified procedures, AbbVie may engage with 
study site personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity of care.  This 
may include alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab), and shipping investigational 
product and/or supplies direct to subjects to ensure continuity of treatment where allowed.  In all cases, 
these alternative measures must be allowed by local regulations and permitted by IRB/IEC.  Investigators 
should notify AbbVie if any urgent safety measures are taken to protect the subjects against any 
immediate hazard.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s) including the archiving of essential documents.  During the COVID-19 pandemic, remote 
monitoring of data may be employed if allowed by the local regulatory authority, IRB/IEC, and the study 
site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
Page 45 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
START AND COMPLETION OF THE STUDY
The start-of-study is defined as the date of the first site activated.
The end-of-study is defined as the date of the last subject's last visit or date of last follow-up contact 
with the subject, whichever is later, in the last country where the study was conducted.
12
REFERENCES
1.
Mughal TI, Vaddi K, Sarlis NJ, et al. Myelofibrosis-associated complications: pathogenesis, clinical 
manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89-101.
2.
Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. A pooled analysis of overall survival in COMFORT-I 
and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. 
Haematologica. 2015;100(9):1139-45.
3.
Santos FP, Verstovsek S. What is next beyond janus kinase 2 inhibitors for primary myelofibrosis? 
Curr Opin Hematol. 2013;20(2):123-9.
4.
Meyer SC. Mechanisms of Resistance to JAK2 Inhibitors in Myeloproliferative Neoplasms. Hematol
Oncol Clin North Am. 2017;31(4):627-42.
5.
Zeuner A, Pedini F, Francescangeli F, et al. Activity of the BH3 mimetic ABT-737 on polycythemia 
vera erythroid precursor cells. Blood. 2009;113(7):1522-5.
6.
Waibel M, Solomon VS, Knight DA, et al. Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant 
JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors. Cell Rep. 
2013;5(4):1047-59.
7.
Guo J, Roberts L, Chen Z, et al. JAK2V617F drives Mcl-1 expression and sensitizes hematologic cell 
lines to dual inhibition of JAK2 and Bcl-xL. PLoS One. 2015;10(3):e0114363.
8.
Will B, Siddiqi T, Jorda MA, et al. Apoptosis induced by JAK2 inhibition is mediated by Bim and 
enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells. Blood. 
2010;115(14):2901-9.
9.
Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International 
Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European 
LeukemiaNet (ELN) consensus report. Blood. 2013;122(8):1395-8.
10. Thiele J, Kvasnicka HM, Facchetti F, et al. European consensus on grading bone marrow fibrosis and 
assessment of cellularity. Haematologica. 2005;90(8):1128-32.
Page 46 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
11. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for 
myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 
2018;8(2):15.
12. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis 
treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 
2013;7:13-21.
13. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic 
Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, 
platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392-7.
14. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines on Myeloproliferative 
Neoplasms Version 3. 2019.
15. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for 
myelofibrosis. N Engl J Med. 2012;366(9):799-807.
16. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in 
primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative 
Neoplasms Research and Treatment). Blood. 2010;115(9):1703-8.
Page 47 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
Adverse event
Ag
antigen
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC0-12
Area under the curve from 0 to 12 hours
BCL-2
B-cell lymphoma-2
BCRP
Breast cancer resistance protein
BET
Bromodomain and extra-terminal motif
BH3
B-cell lymphoma 2 homology 3
BUN
Blood urea nitrogen
CI
Confidence interval
CL/F
Apparent oral clearance
CLL
Chronic lymphocytic leukemia
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus disease 2019
CSF
Colony stimulating factor
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DIPSS+
Dynamic International Prognostic Scoring System Plus
DNA
Deoxyribonucleic acid
DSUR
Development Safety Update Report
DTP
Direct-to-patient
EC50
Concentration required for 50% effect
ECG
Electrocardiogram
eCOA
Electronic clinical outcome assessments
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
Page 48 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
EDC
Electronic data capture
ELN
European LeukemiaNet
EORTC
European Organisation for Research and Treatment of Cancer
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels Health State Instrument
ESR
Erythrocyte sedimentation rate
FFPE
Formalin-fixed paraffin-embedded
FISH
Fluorescence In Situ Hybridization 
FLT3
FMS-like tyrosine kinase 3
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
Hb
Hemoglobin
HBV
Hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HMR
High molecular risk
HR
Hazard ratio
HRQoL
Health-related quality of life
HSCT
Hematopoietic stem cell transplantation
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IDMC
Independent data monitoring committee
IEC
Independent ethics committee
IGRA
Interferon-gamma release assay
IMP
Investigational medicinal product
INR
International normalized ratio
Int
Intermediate
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IWG
International Working Group
Page 49 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
JAK1
Janus kinase 1
JAK2
Janus kinase 2
LDL
Low-density lipoprotein
LFS
leukemia-free survival
LMWH
Low molecular weight heparin
MCL-1
Myeloid cell leukemia 1
MedDRA
Medical Dictionary for Regulatory Activities
MF
Myelofibrosis
MFSAF
Myelofibrosis Symptom Assessment Form
MRI
Magnetic resonance imaging
mRNA
messenger ribonucleic acid
NCI
National Cancer Institute
NRS
Numeric rating scale
NSAID
nonsteroidal anti-inflammatory drug
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PCP
Pneumocystis carinii pneumonia
PET
Post essential thrombocythemia
PFS
Progression-free survival
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
P-gp
P-glycoprotein
PK
Pharmacokinetic
Plt
Platelet
PMF
Primary myelofibrosis
PPD
Purified protein derivative
PPV
Post polycythemia vera
PR
Partial remission
PRO
Patient-reported outcome
PROMIS
Patient-Reported Outcomes Measurement Information System
PT
Prothrombin time
Q12
Every 12 (weeks)
Q24
Every 24 (weeks)
QLQ
Quality of life questionnaire
Page 50 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
QoL
Quality of life
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia's formula
RBC
Red blood cell
RNA
Ribonucleic acid
RPTD
Recommended Phase 2 dose
RSI
Reference Safety Information
SAE
Serious adverse event
SAP
Statistical analysis plan
SAR
Serious adverse reaction
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SDAC
Statistical data analysis center
SF
Short form
SMF
Secondary myelofibrosis
SmPC
Summary of product characteristics
SOC
System organ class
SSRI
Selective serotonin re-uptake inhibitors
SUSAR
Suspected unexpected serious adverse reaction
SVR35
At least 35% spleen volume reduction from baseline
SVR35W24
At least 35% reduction in spleen volume at Week 24 from baseline
TA MD/SD
Therapeutic Area Medical Director/Scientific Director
TB
Tuberculosis
TCV
Treatment completion visit
TSS
Total symptom score
TSS50W24
At least 50% reduction in total symptom score at Week 24 from baseline
ULN
Upper limit of normal
USA
United States of America 
USPI
United States prescribing information
v
Version
VAS
Visual analogue scale
V/F
Apparent volume of distribution
WBC
White blood cell
WHO
World Health Organization
Page 51 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-191:  A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Navitoclax in 
Combination with Ruxolitinib Versus Ruxolitinib in Subjects with Myelofibrosis (TRANSFORM-1)
Protocol Date:  23 March 2023
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
Page 52 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Study Leadership
Clinical Study Leadership
TA Oncology
Statistics
Health Economics & Outcomes 
Research
Patient Experience Data & Strategy
Clinical Development Oncology
Medical Writing
Page 53 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities.  The individual activities are described in detail in the 
Operations Manual.
Page 54 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX E. WORLD HEALTH ORGANIZATION DIAGNOSTIC 
CRITERIA FOR PRIMARY MYELOFIBROSIS
Primary Myelofibrosis (PMF) – Overt PMF
Major Criteria
1.
Megakaryocyte proliferation and atypiaa accompanied by either reticulin and/or 
collagen fibrosis (Grade 2 or 3).
2.
Not meeting WHO criteria for BCR-ABLI + CML, PV, ET, MDS, or other myeloid 
neoplasm.
3.
Presence of JAK2, CALR, or MPL mutation or in the absence, the presence of another 
clonal markerb or absence of evidence for reactive BM fibrosis.c
Minor Criteria
Presence of one or more of the following confirmed in two consecutive determinations:

Anemia not attributed to a comorbid condition

Leukocytosis ≥11 × 109/L

Palpable splenomegaly

LDH levels above the upper limit of the institutional reference range

Leukoerythroblastosis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807384/
a.
Small-to-large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei 
and dense clustering.
b.
In the absence of any of the three major clonal mutations, the search for the most frequent accompanying 
mutations (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease.
c.
BM fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell leukemia, or 
other lymphoid neoplasm, metastatic malignancy or toxic (chronic) myelopathies.
Page 60 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX F. DYNAMIC INTERNATIONAL PROGNOSTIC 
SCORING SYSTEM (DIPSS) AND DIPSS PLUS 
(DIPSS+) FOR SURVIVAL IN PRIMARY 
MYELOFIBROSIS
DIPSS16
DIPSS+16
Page 61 of 125
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX G. SAMPLE LIST OF EXCLUDED AND CAUTIONARY 
MEDICATIONS
Prohibited Medications
Anticoagulation Therapy (Excluded)
warfarin (Coumadin) and coumarin derivatives e.g., 
phenprocoumon
fondaparinux (Arixtra)
heparina
melagatran/ximelagatran
rivaroxaban (Xarelto) 
apixaban (Eliquis)
Antiplatelet (Excluded)
acetylsalicylic acid (aspirin) > 100 mg once daily
aspirin/extended release dipyridamole (Aggrenox)
clopidogrel (Plavix)
dipyridamole (Persantine)
ticlopidine (Ticlid)
tirofiban (Aggrastat)
Potential prolongation of prothrombin time (PT) 
(Excluded)
disulfiram
Cautionary Medications
Strong CYP3A Inhibitors (Cautionary)b
boceprevir
clarithromycin
cobicistat
conivaptan
danoprevir/ritonavir
elvitegravir/ritonavir
idelalisib
indinavir
itraconazole
ketoconazole
lopinavir/ritonavir
mibefradil
nefazodone
nelfinavir
paritaprevir/ritonavir
Posaconazole
ritonavir
saquinavir
telaprevir
telithromycin
tipranavir/ritonavir
troleandomycin
voriconazole
Strong CYP3A Inducers (Cautionary)b
apalutamide
avasimibe
carbamazepine
enzalutamine
mitotane
phenytoin
rifampin
St John's wort
Page 62 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
CYP2C8 Substrates (Cautionary)b,c
amiodarone
amodiaquine
cerivastatin
chloroquine
lovastatind
paclitaxel (Taxol)
pioglitazone
repaglinide
rosiglitazone
simvastatin (Zocor)d
troglitazone
CYP2C9 Substrates (Cautionary)b
fluvastin
glipizide
irbesartan
losartan
phenytoin
sulfamethoxazole
sulfinpyrazone
tolbutamide
torsemide
P-gp Substrates (Cautionary)b
dabigatran etexilate
digoxin
fexofenadine
BCRP Substrates (Cautionary)b
rosuvastatin
sulfasalazine
P-gp Inhibitors (Cautionary)b
amiodarone
carvedilol
clarithromycin
dronedarone
itraconazole
lapatinib
lopinavir and ritonavir
propafenone
quinidine
ranolazine
ritonavir
saquinavir
telaprevir
tipranavir
ritonavir
verapamil
BCRP Inhibitors (Cautionary)b
curcumin
cyclosporine A
eltrombopag
P-gp Inducers (Cautionary)e
rifampin
phenytoin
carbamazepine
St John's wort
quercetin
curcumin
BCRP Inducers (Cautionary)f
efavirenz
rifampin
phenytoin
quercetin
curcumin
omeprazole
imatinib
Page 63 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Anticoagulation Therapy (Cautionary)
low molecular weight heparin
dalteparin (Fragmin)
enoxaparin (Lovenox)
tinzaparin (Innohep)
SSRIs and SNRIs (Cautionary)
citalopram (Celexa)
escitalopram (Lexapro)
fluoxetine (Prozac)
paroxetine (Paxil)
sertraline (Zoloft)
duloxetine (Cymbalta)
vortioxetine (Trintellix)
 venlafaxine (Effexor) 
Desvenlafaxine (Pristiq)
NSAIDSg (Cautionary)
Aspirin > 100 mg daily
Celecoxib
Diclofenac
Diflunisal
Etodolac
Ibuprofen
Indomethacin
Ketoprofen
Nabumetone
Naproxen
Oxaprozin
Salsalate
Sulindac
Tolmetin
CYP = cytochrome P450; P-gp = P-glycoprotein; SSRI = Selective serotonin re-uptake inhibitors
a.
Heparin may be used for patency of a central venous catheter and temporary use for prophylaxis of deep vein thrombosis.
b.
This is not an exhaustive list.  For an updated list, see the following link 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.
htm.
c.
Only certain statins qualify as CYP2C8 substrates.
d.
Significant increase in area under the curve (AUC) by co-administration of gemfibrozile, a potent CYP2C8 inhibitor.  
However, the involvement of CYP2C8 is unclear.
e.
This is not an exhaustive list.  Elmeliegy M et al, Clinical Pharmacokinetics (2020);59:699-714.
f.
This is not an exhaustive list.  Gameiro M et al, Molecules (2017);22(4):600.
g.
Certain NSAIDS are also CYP2C9 substrates. NSAIDS are allowed for limited use only if platelets >100 x 109/L.
Page 64 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX H. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
28 February 2020
Version 2.0
24 June 2020
Version 2.1 (France Only)
01 September 2020
Version 2.2 (Sweden Only)
09 September 2020
Version 2.3 (United Kingdom Only)
10 September 2020
Version 2.4 (Belgium Only)
23 September 2020
Version 2.4.1 (Belgium Only)
13 October 2020
Version 3.0
05 November 2020
Version 4.0
27 May 2021
Administrative Change 1
24 November 2021
Version 5.0
03 February 2022
Version 6.0
31 March 2022
Administrative Change 2 (Japan Only)
12 July 2022
The purpose of this version is to correct minor clerical/typographical errors for consistency throughout 
the protocol and the following:

Updated Protocol Section 3.2 to clarify the second efficacy endpoints of the change in TSS and 
change in physical functioning.  Overall response of clinical improvement was also removed as a 
secondary efficacy endpoint. 

Updated Protocol Section 3.3 to include additional exploratory endpoints. 

Updated Protocol Section 5.5 to include additional information about continuation of study 
treatment for subjects with disease progression or relapse. 

Updated Protocol Section 5.5 to clarify guidance on study drug interruption in case of COVID-19 
confirmation/suspicion during study treatment period. 

Updated Protocol Section 6.2 to correct typo error in Table 1. for ruxolitinib dose adjustment 
guidelines. 

Updated Protocol Section 7.3 to clarify that stratification factors for stratified analyses in the 
primary efficacy analysis can be found in the SAP. 

Updated Protocol Section 7.3 to define changes in TSS and physical functioning for secondary 
efficacy analysis. Additionally, it was clarified that a linear mixed effects model will be used for
all continuous patient-reported outcome endpoints unless otherwise specified.
Page 65 of 125
 

  
STUDY M16-191  |  Version 7.0  |  EudraCT 2020-000097-15
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Updated Protocol Section 7.6 to reflect changes in secondary efficacy endpoints and their 
rankings. 

Updated Protocol Section 7.7 to include information on planned OS analyses.

Added Section 5.5 in the Operations Manual in order to identify "Drugs used in the Clinical Trial"
in accordance with revisions to local guidance in Japan.
Page 66 of 125