Zanubrutinib, a Second Generation BTK Inhibitor, in Anti-MAG Antibody Neuropathy: a Phase II Italian Multicenter Clinical Trial (MAZINGA)
Phase: PHASE2
Conditions: Anti-MAG IgM-associated Demyelinating Polyneuropathy
Sponsor: Azienda Ospedaliera di Padova

Protocol No. MAZ-01, Clinical Study Protocol   
 
 
Azienda Ospedale - Università Padova 
 
Protocol MAZINGA v2.1 EN 03DEC2025 
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Clinical Study Protocol 
 
ZANUBRUTINIB, A SECOND GENERATION BTK INHIBITOR, IN ANTI-MAG 
ANTIBODY NEUROPATHY: A PHASE II ITALIAN MULTICENTER CLINICAL TRIAL 
(MAZINGA) 
 
 
Eu CT number 2025-523091-23-00 
 
Protocol Number: “MAZ-01” 
 
Protocol abbreviation: MAZINGA 
 
Date and version of the Protocol:  v2.1 03DEC2025 
 
Sponsor: Azienda Ospedale - Università Padova, via N Giustiniani 1, 35128, Padova, Italia 
 
Study Principal Investigator:  Dr Andrea Visentin, UOC Ematologia - Azienda Ospedale - Università 
Padova, via N Giustiniani 1, 35128, Padova 
 
Coordinating Center: Azienda Ospedale - Università Padova - U.O.C. Ematologia 
 
 
 
Conduct: Conducted in compliance with this Protocol, International Conference on Harmonization (ICH) 
guidelines on Good Clinical Practice (GCP), with Regulation EU No. 536/2014 on Clinical Trials, and in 
accordance with local regulatory requirements. 
 
 
CONFIDENTIALITY STATEMENT 
 
This document is confidential and contains proprietary information of Azienda Ospedale - Università 
Padova. It may not—in full or in part —be used, transmitted, reproduced, published, or distributed to any 
person without the express written permission of Azienda Ospedale - Università Padova. 
 
 
 

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PROTOCOL APPROVAL SIGNATURE PAGE 
 
I have read and understand the contents of V2.1 of this clinical study Protocol for Study No. MAZ-01 dated 
03 December 2025 and I agree to meet all the obligations of the Sponsor as detailed in all applicable 
regulations and guidelines. In addition, I will inform the Principal Investigator and all other Investigators of 
all relevant information that becomes available during the conduct of this Study. 
 
 
Date………… 
  
Approved by 
 
_______________________________ 
Dr  
 
 
 
 
04/12/2025
     ANDREA VISENTIN

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PRINCIPAL INVESTIGATOR’S PROTOCOL SIGNATURE PAGE 
 
I have read and understood the contents of Version 2.1 of this clinical protocol for Study No. MAZ-01 dated 
03 Dec 2025 and will adhere to the study requirements as presented, including all statements regarding 
confidentiality. In addition, I will conduct the Study in accordance with current Good Clinical Practices and 
applicable EMA and local regulatory requirements. 
 
Printed Name: 
Title: 
Institution: 
Address: 
Email: 
Phone: 
 
 
_________________________________  
 
 
 
 
______________ 
Principal Investigator’s Signature 
 
 
 
 
 
 
 
Date 
 
 
 

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TABLE OF CONTENTS 
 
ZANUBRUTINIB, A SECOND GENERATION BTK INHIBITOR, IN ANTI-MAG ANTIBODY NEUROPATHY: A 
PHASE II ITALIAN MULTICENTER CLINICAL TRIAL (MAZINGA) .......................................................................................... 9 
1 
Introduction .......................................................................................................................................................................................... 9 
2 
Objective of the trials ..................................................................................................................................................................... 10 
3 Endpoints of the trial ........................................................................................................................................................................... 10 
4 Selection of patients ............................................................................................................................................................................. 11 
5 Study design ............................................................................................................................................................................................ 13 
6 Risks and benefits assessment ........................................................................................................................................................ 15 
7 Treatment ................................................................................................................................................................................................. 15 
8 Pregnancy and contraception .......................................................................................................................................................... 20 
9 Duration of the study ........................................................................................................................................................................... 21 
10 Discontinuation of study treatment ........................................................................................................................................... 21 
11 Drug supply Accountability ............................................................................................................................................................ 22 
12 Criteria of evaluation of response ............................................................................................................................................... 22 
13  Statistical considerations ............................................................................................................................................................... 24 
14 Independent data monitoring committee................................................................................................................................ 27 
15 Quality of life assessment................................................................................................................................................................ 27 
16 Translational research Rationale ................................................................................................................................................ 27 
17 List of recruiting Italian centers ................................................................................................................................................... 28 
18 Adverse Events Definition .............................................................................................................................................................. 28 
19. Quality assurance Control of data consistency ..................................................................................................................... 32 
20 Ethical considerations and Patient protection, Regulatory and legal obligations ................................................. 33 
21 Administrative responsibilities The Study Principal Investigators ............................................................................. 33 
22. Trial sponsorship and financing ................................................................................................................................................. 34 
23. Trial insurance .................................................................................................................................................................................... 34 
24. Publication policy, study report and archiving of study documentation .................................................................. 34 
25. Investigator authorization procedure ...................................................................................................................................... 35 
26. Patient registration procedure .................................................................................................................................................... 36 
27. Forms and procedures for collecting data .............................................................................................................................. 36 
28 Monitoring procedures during the study ................................................................................................................................. 36 
 
 
 

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LIST OF APPENDICES 
 
APPENDIX A: REFERENCES 
 
 
 
 
 page 38 
APPENDIX B: NEUROLOGICAL SCALES  
 
 
page 40 
APPENDIX C: STUDY DRUGS TOXICITIES  
 
 
page 47 
APPENDIX D: Interaction with other  
medicinal products and other forms of interaction  
 
page 49 
APPENDIX E: CENTRALIZATION OF SAMPLES 
 
page 52 
APPENDIX F: World Medical Association  
Declaration of Helsinki  
 
 
 
 
page 55 
 
 
 

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LIST OF ABBREVIATIONS  
 
ACBP Adult Subjects of Childbearing Potential 
AE Adverse Event 
AESI Adverse Event of Special Interest 
AIFA Agenzia Italiana del Farmaco 
ALT Alanine Aminotransferase 
ANC Absolute Neutrophil Count 
ASaT All-subject-as-treated 
ASCO American Society of Clinical Oncology 
AST Aspartate Aminotransferase 
AUC Area Under the Curve 
BM Bone Marrow 
BTK Bruton’s Tyrosine Kinase 
CANOMAD Chronic Ataxic Neuropathy, Ophthalmoplegia, IgM Monoclonal Abnormal protein, Disialosyl 
antibodies 
CBC Complete Blood Count 
cfDNA Cell-Free DNA 
CIOMS Council for International Organizations of Medical Sciences 
CLL Chronic Lymphocytic Leukemia 
CMAP Compound Action Muscle Potential 
CR Complete Response 
CRF Case Report Form 
CRi Complete Response with Incomplete Bone Marrow Recovery 
CSF cerebrospinal fluid 
CTCAE Common Terminology Criteria for Adverse Event 
CXCR4 Chemokine Receptor type 4 
CYP3A Cytochrome P450, family 3, subfamily A 
ddPCR Droplet Digital Polymerase Chain Reaction 
DML Distal Motor Latency 
EC Ethics Committee 
ECG Electrocardiogram 
ECOG Electrocorticography 
EFNS European Federation of Neurological Societies 
EKG electrocardiogram 
EMA European Medicines Agency 
EMG Electromyography 
ENG Electroneurography 
EU European Union 
GCP Good Clinical Practice 
Gdna Genomic DNA 
GMP Good Manufacturing Practice 
GVP Good Pharmacovigilance Practice 
HBcAb Hepatitis B core Antibody 
HBsAg Hepatitis B surface Antigen 
HBV Hepatitis B Virus 
HCV Hepatitis C Virus 

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ICF Informed Consent Form 
ICH International Council for Harmonisation 
IgM Immunoglobulin M 
INCAT Inflammatory Neuropathy Cause and Treatment 
IRB Institutional Review Board 
I-RODS Inflammatory Rasch-Built Overall Disability Scale 
ISS INCAT Sensory Sum Score 
IU International Unit 
LDH Lactate Dehydrogenase 
MAG Myelin-associated Glycoprotein 
MCV Motor Conduction Velocity 
MGUS Monoclonal Gammopathy of Undetermined Significance 
MRC Medical Research Council 
MYD88 Myeloid Differentiation Primary Response  
MZL Marginal Zone Lymphoma 
NRS Numeric Rating Scale 
NRS Numeric Rating Scale 
ONLS Overall Neuropathy Limitations Scale 
ORR Overall Response Rate 
OS Overall Survival 
PLCG2 Phospholipase C Gamma 2 
PNS Peripheral Nerve Society 
POEMS Patient-Oriented Evidence that Matters 
PQC Product Quality Complaint 
PR Partial Response 
QOL Quality of Life 
QPPV Qualified Person for Pharmacovigilance 
SAE Serious Adverse Event 
SCV Sensory Conduction Velocity 
SNAP Sensory Nerve Action Potential 
SUSAR Suspected Unexpected Serious Adverse Reaction 
TLI Terminal Latency Index 
TP53 Tumor Protein P53 
U.O.C Unità Operative Complessa 
ULN Upper Limit of Normal 
VGPR Very Good Partial Response 
WBC White Blood Cells 
WHO World Health Organization 
WM Waldenstrom Macroglobulinemia 
WMA World Medical Association 
WOCBP Women of Childbearing Potential 
 
 

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ZANUBRUTINIB, A SECOND GENERATION BTK INHIBITOR, IN ANTI-MAG ANTIBODY 
NEUROPATHY: A PHASE II ITALIAN MULTICENTER CLINICAL TRIAL (MAZINGA) 
1  Introduction 
Monoclonal gammopathy of neurological significance is an emerging often unrecognized condition 
characterized by several facets, of which polyneuropathy with antibodies to the myelin-associated 
glycoprotein (MAG) is the most common entity. Anti-MAG antibody polyneuropathy is a rare and disabling 
neuropathy, orphan of specific and effective therapies. Patients are usually elderly presenting with distal, 
symmetric, sensory involvement with gait ataxia and postural tremor at upper limbs. Motor impairment 
occurs late in the course of the disease. Although slowly progressive, the neuropathy may become severely 
disabling after several years (25% at 10 years, 50% after 15 years)1,2 sometimes requiring the use of a 
wheelchair. All patients have an IgM monoclonal paraprotein that only in half of cases is related to a 
hematological malignancy such as Waldenstrom macroglobulinemia (WM)3, marginal zone lymphoma 
(MZL) or chronic lymphocytic leukemia (CLL). 
Anti-MAG antibodies have a pathogenic role, since pathological studies on nerve biopsies show segmental 
demyelination with IgM M-protein and complement deposition on nerve myelin4. Moreover, serum from 
patients with anti-MAG antibody neuropathy induces demyelination5 and also a demyelinating neuropathy 
in experimental model6. These considerations have prompted the use of immunologic therapies in patients 
(such 
as 
steroids, 
plasma-exchange, 
cyclophosphamide, 
azathioprine, 
interferon, 
high 
dose 
immunoglobulin) but with disappointing results7. Some open pilot trials have addressed the effect of 
rituximab on IgM paraproteinemic neuropathies. In particular, the Italian peripheral nerve study group 
treated 13 patients with anti-MAG antibody polyneuropathy showing a reduction of the anti-MAG antibody 
titers in more than 50% of subjects with mild improvement in clinical status, especially in the sensory 
items8. IgM MGUS and WM-associated anti-MAG neuropathies display similar response to rituximab 
therapy, with less than 50% of patients reporting clinical benefit9. 
Rituximab has been assessed in two randomized controlled trials10,11 with controversial results, both of 
them, however, accounting only for MGUS patients, WM being an exclusion criteria. The first study enrolled 
26 patients undergoing a single course of rituximab or placebo. In the 13 patients treated with rituximab, 
4/13 improved by ≥1 point on the Inflammatory Neuropathy Cause and Treatment (INCAT) disability leg 
score, and the majority of them (69%) showed significant improvement in the ‘time to walk 10 m’)10. The 
second study that included 54 patients treated with a single course of rituximab or placebo.11 Changes were 
observed in the rituximab group only in some secondary outcome measures, including improvement by ≥2 
points on the INCAT disability scale, improvement in the self-evaluation scale and in two sub-scores of the 
Short Form 36 questionnaire11. A comparison between the two studies is difficult, because of the different 
inclusion criteria and the different disease duration before starting treatment (12.9 yrs in the first study vs 
3.8 in the second study, respectively). A Cochrane review12 concluded that there is inadequate reliable 
evidence from trials of immunotherapies in anti-MAG paraproteinemic neuropathy to recommend any 
treatment. The meta-analysis of two clinical trials, recruiting a total of 80 patients, provides evidence of 
improvement in 50-60% patients of disability scale and self-evaluation, reduction of lymphocytes, IgM 
levels and anti-MAG titer with rituximab single agent11. For these reasons, rituximab has become the 
standard treatment of anti-MAG neuropathy. A recent study assessed rituximab in 23 patients with anti-
MAG neuropathy. Authors found that some neurophysiological variables, such as ulnar nerve Terminal 
Latency Index and distal motor latency and ulnar nerve sensory nerve action potential (SNAP) amplitude 
might be useful for monitoring the efficacy of Rituximab in these patients13. 
 
Previous human experience 
Ibrutinib, the first in class Bruton’s tyrosine kinase (BTK) inhibitor, has significantly improved the 
prognosis and management of patients with B-cell malignancies with an optimal safety profile when used 
as single agent14 or in combination with rituximab15. Treon et al16 reported a reduction of anti-MAG 
antibody titer and clinical improvement in 3 patients with WM and concomitant anti-MAG antibody 
neuropathy. While patients with anti-MAG antibody neuropathy and a B-cell lymphoma (20-25% of cases) 
could benefit from therapy with ibrutinib and/or rituximab, the majority (75-80%) with IgM monoclonal 

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component of unknown significance (MGUS) could not. Moreover, recent studies on the biology of the 
disease showed that patients with anti-MAG antibody polyneuropathy are characterized by recurrent 
MYD88L265P mutations but very low incidence of CXCR4whim and TP53 mutations17. This molecular profile 
is predictive of high and durable response rates to ibrutinib in WM18. Furthermore, molecular remission of 
MYD88 recently emerged as an independent predictor of progression-free survival in patients with WM 
treated with rituximab-based chemo-immunotherapy19. 
Recently, Castellani et all report the clinical efficacy of ibrutinib in 3 MYD88-mutated patients with WM 
anti-MAG peripheral neuropathy20. Treatment was well tolerated, and all 3 patients reported a subjective 
early benefit during ibrutinib treatment as well as an improvement of INCAT disability and sensory scores. 
Zanubrutinib is a second generation BTK inhibitor, characterized by a more selective kinase profile 
compared to ibrutinib, that proved to be highly active as well as better tolerated in several B-cell 
hematological malignancies. In particular, the Aspen21 study compared zanubrutinib and ibrutinib in 
patient with WM within a phase 3 clinical trials. Twenty-nine (28%) zanubrutinib patients and 19 (19%) 
ibrutinib patients achieved a VGPR (very good partial response). Duration of response and progression free 
survival of zanubrutinib was superimposable to ibrutinib. However, atrial fibrillation, bruising, diarrhea, 
muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less 
common among zanubrutinib recipients. In a subgroup analysis, zanubrutinib proved its activity in MYD88-
wild type patients22. At a median follow-up of 17.9 months, 7 of 26 MYD88-wild type patients (27%) had 
achieved a VGPR and 50% at least a partial response. At 18 months, the estimated progression-free survival 
and overall survival rates were 68% and 88%. Furthermore, zanubrutinib prove to be highly active in CLL 
and MZL23,24. 
These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but 
zanubrutinib treatment was associated with a trend toward better response quality, in particular in MYD88 
wild type patients, and less toxicity, particularly the cardiovascular toxicity. 
With this background, we would like to perform a multicenter, open label, single arm phase IIA trial to 
evaluate the activity, safety and tolerability of zanubrutinib in patients with symptomatic IgM related anti-
MAG antibody neuropathy. 
 
 
2 Objective of the trials  
Primary objective 
To investigate whether 12 months zanubrutinib treatment led to an improvement of at least 1 point in 
at least 2 neurological scales as a decrease for the Overall Neuropathy Limitations Scale (ONLS), INCAT 
disability, INCAT sensory sum scores (ISS), but an increase with the MRC sum and I-RODS functional 
score. 
Secondary objectives 
● To evaluate ENG/EMG improvement, in particular a reduction of distal motor latency, or an increase 
of terminal latency index or an increase of sensory nerve action potential amplitude (see criteria of 
evaluation) after zanubrutinib treatment at 12, 24 and 48 months; 
● To evaluate the efficacy by hematological overall response rates, event free survival, time to 
progression (defined as worse of at least 1 point in two neurological scales), overall survival; 
● To study the safety profile of zanubrutinib in patients with anti–MAG antibody polyneuropathy. 
Exploratory objectives 
● To evaluate the quality of life or patients by FACT-GOG-NTX-13 QOL questionnaire; 
● To identify any correlation between neurologic response (assessed by the neurological scaled 
mentioned in the primary endpoint) and hematologic overall response (CR, VGPR, PR) at 24 and 48 
months, event free survival, time to progression and overall survival with demographic, clinical, 
molecular and pathological (MGUS vs lymphoma) features of the patients at baseline; 
● To evaluate the reduction of MYD88 mutational burden by cf-DNA during treatment; 
To evaluate the emergence of BTK and PLCG2 mutational status in relapsing patients. 
 
3 Endpoints of the trial 

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Primary endpoint 
The proportion of patients with neurological improvement defined as improvement of at least 1 point 
in at least 2 neurological scales (a decrease of the ONLS, INCAT disability, INCAT sensory sum scores 
(ISS), but an increase of MRC sum and I-RODS functional score) at 12 months of zanubrutinib 
treatment. 
Secondary endpoints 
● the proportion of patients with neurological improvement after 24 and 48 months of zanubrutinib; 
● the proportion of patients with ENG/EMG improvement since the baseline, assessing decrease of 
distal motor latency, increase of terminal latency index, increase of sensory nerve action potential 
amplitude (see criteria of evaluation) at upper limbs after zanubrutinib treatment at 12, 24 and 48 
months; 
● levels of monoclonal protein, IgM and of anti-MAG antibody titers at 12, 24 and 48 months. 
● Type, frequency and severity of adverse events, severe adverse event and adverse event of special 
interest with zanubrutinib in patients with anti–MAG antibody polyneuropathy; 
● Overall response rate, defined as the proportion of patients achieving complete response (CR), 
complete response rate with incomplete bone marrow recovery (CRi), very good partial response 
(VGPR), partial response according to guidelines; 
● Event free survival, defined as time from the start of therapy to relapse or death or start of a new 
therapy (event) or last known follow-up (censured); 
● Time to progression, defined as time from the start of therapy worse of neurological symptoms 
defined as worse of least 1 point in at least 2 neurological scales such as Overall Neuropathy 
Limitations Scale (ONLS), INCAT disability, INCAT sensory sum scores (ISS), MRC sum score, I-
RODS functional score after the nadir 
● overall survival, defined as time from the start of therapy to death (event) or last known follow-up 
(censured). 
Exploratory endpoints 
● Quality of life will be assessed by FACT-GOG-NTX-13 QOL questionnaire every 3 months 
during the first year and then every 6 months; 
● correlation between neurologic responses (assessed by the neurological scaled reported for the 
primary endpoint) and hematologic overall response (CR, VGPR, PR) at 24 and 48 months, event 
free survival, time to progression and overall survival with demographic, clinical,molecular and 
and pathological (MGUS vs lymphoma) features of the patients at baseline; 
● reduction of MYD88 mutational burden by cf-DNA during treatment; 
● BTK and PLCG2 mutation status in relapsing patients. 
 
4 Selection of patients 
Inclusion criteria 
● Age ≥18 years; 
● diagnosis of anti-MAG antibody polyneuropathy; 
● Neurophysiological (ENG/EMG) evidence of a demyelinating polyneuropathy with evidence of 
disproportionately prolonged distal motor latency in one or more nerves -excluding the median nerve 
if related to carpal tunnel syndrome- [Joint Task Force of the EFNS and the PNS, 2010]. 
● IgM monoclonal protein underlying MGUS (based on the WHO definition of clonal lympho- plasmocytes 
<10%), Waldenstrom macroglobulinemia (based on the WHO definition of clonal lympho-plasmocytes 
≥10%), marginal zone lymphoma, chronic lymphocytic leukemia or low- grade lymphoma not 
otherwise specified; 
● Presence of anti MAG antibodies (titer ≥ 7.000 BTU); 
● Neurophysiological (ENG/EMG) evidence of demyelinating polyneuropathy; 
● ONLS at lower limbs at least ≥1 and/or INCAT ≥2. 
● Adequate bone marrow function as defined by: 
o Absolute neutrophil count (ANC) ≥ 1000/mm3, except for patients with bone marrow 
involvement in which ANC must be ≥ 500/mm3  

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o Platelet ≥ 75,000/mm3, except for patients with bone marrow involvement in which the 
platelet count must be ≥ 30,000/mm3  
● Women should avoid becoming pregnant while taking Brukinsa and for up to 1 month after ending 
treatment. Male patients with a female partner of childbearing potential are eligible if vasectomized or 
if they agree to the use of barrier contraception with other methods described above during the study 
treatment period and for ≥ 90 days after the last dose of zanubrutinib. 
● Women of childbearing potential (WOCBP1) should avoid becoming pregnant while taking Brukinsa and 
for up to 1 month after ending treatment. Either commit to true abstinence from heterosexual contact 
(which must be reviewed on a monthly basis and source documented) or agree to use highly effective 
methods of contraception: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with the 
inhibition of ovulation 
- 
Oral, intravaginal, or transdermal 
• 
Progestogen-only hormonal contraception associated with the inhibition of ovulation 
- 
Oral, injectable, implantable 
• 
An intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatment, starting the day before the first dose of 
study treatment, for the duration of the study, and for ≥ 90 days after the last dose of 
zanubrutinib, for ≥ 28 days after the last dose of lenalidomide, or according to the approved 
obinutuzumab and rituximab product/prescribing information, whichever is later). Total 
sexual abstinence should only be used as a contraceptive method if it is in line with the patients’ 
usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of exposure to 
investigational medicinal product, and withdrawal are not acceptable methods of 
contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) is not 
considered a highly effective method of contraception, and, if used, this method must be used in combination 
with another acceptable method listed above. 
For patients using hormonal contraceptives such as birth control pills or devices, a second barrier method 
of contraception (eg, condoms) must be used. 
● Male patients with a female partner of childbearing potential are eligible if abstinent, vasectomized or if 
they agree to the use of barrier contraception with other methods or agree to use a condom during sexual 
contact with a pregnant women or a women of childbearing potential during the study treatment period 
and for ≥ 90 days after the last dose of zanubrutinib. 
________________________ 
1 WOCBP is a woman who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral 
oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive 
months). 
  
 
Exclusion criteria 
● Previous treatment with BTK inhibitors 
● Aggressive non-Hodgkin lymphoma or IgM multiple myeloma 
● Evidence of moderate or severe motor nerve axonal damage, defined when occurring diffuse 
polyneuropathic denervation or a recruitment pattern lower than intermediate in ≥50% of muscles 
examined, and/or INCAT at lower limbs ≥4. 
● ECOG >3 
● Use of strong CYP3A inducers within 14 days prior to the first dose of zanubrutinib (see Drug-

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interaction section). 
● creatinine clearance <30mL/min 
● Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine 
aminotransferase (ALT)/serum glutamic pyruvic transaminase> 2.5 × upper limit of normal (ULN); 
Serum total bilirubin >2 x ULN. 
● presence of other possible causes of neuropathy, such as active HCV infections, diabetes- neuropathy, 
POEMS syndrome, CANOMAD syndrome, etc. 
● Any co-existing medical or psychological condition that would preclude participation in the study or 
compromise the ability to give informed consent. 
● History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or 
history of spontaneous bleeding requiring blood transfusion or other medical intervention. Requires 
ongoing treatment with warfarin or warfarin derivatives. History of stroke or intracranial 
hemorrhage within 6 months before first dose of study drug 
● Any uncontrolled or clinically significant cardiovascular disease including the following: 
● Myocardial infarction within 6 months before screening 
● Unstable angina within 3 months before screening 
● New York Heart Association class III or IV congestive heart failure   
● History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular 
fibrillation, torsades de pointes)  
● Active fungal, bacterial and/or viral infection requiring systemic therapy 
● Known active infection with HIV, or serologic status reflecting active hepatitis B or C infection as 
follows: 
● Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb).  Patients with 
presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable 
(< 20 IU), and if they are willing to undergo monitoring every 4 weeks for HBV reactivation. 
● Presence of hepatitis C virus (HCV) antibody.  Patients with presence of HCV antibody are eligible if 
HCV RNA is undetectable. 
● Pregnant or lactating women. 
● Vaccination or requirement for vaccination with a live vaccine within 28 days prior to the first dose of 
study drug or at any time during planned study treatment 
● Ongoing alcohol or drug addiction or any psychiatric condition(s) which would compromise ability to 
comply with study procedures. 
● Hypersensitivity to zanubrutinib or any of the other ingredients of the applicable study drugs. 
● Active malignancy or systemic therapy for another malignancy within 3 years, which the except of 
adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, cervical 
carcinoma in situ without evidence of disease, localized prostate cancer without evidence of 
disease. 
 
Discontinuation criteria 
Zanubrutinib must be discontinued: 
- after any grade intracranial hemorrhage;  
- if toxicity cannot be treated to full resolution;  
- if any toxicity recurs 4 times;  
- and in cases of pregnancy. 
 
5 Study design 
This is a prospective phase IIA trial in which patients with polyneuropathy associated with antiMAG 
antibody will be treated with zanubrutinib. Patients with an hematological malignancies 
(waldenstrom macroglobulinemia, marginal zone lymphoma, chronic lymphocytic leukemia) that 
can be treated with zanubrutinib according to the Italian drugs agency (AIFA) approval and 
reimbursement criteria with be treated with zanubrutinib as per clinical practice and patients will 

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be followed prospectively. Instead, patients with MGUS (monoclonal gammopathy of undetermined 
significance) will be treated with zanubrutinib as an investigational medical product within this trial.  
In patients who will improve, defined as improvement of at least 1 point in 2 neurological scales 
(decrease of INCAT, ISS, ONLS, but increase for I-RODS and MRC), or in whom the neuropathy will 
not worse, defined as worse of at least 1 point in 2 neurological scales, zanubrutinib will be continued 
for additional 2 years.  
 
 
 
 
● ENG/EMG at upper and lower limbs at baseline and then every 6 months till month +54; 
● Nerve ultrasound at upper and lower limbs at baseline, after 24 and 48 months of zanubrutinib, 
where available; 
● CBC, biochemistry (hepatic and liver function, serum protein electrophoresis, IgG, IgA, IgM, free light 
chains, 24h-urine protein, Bence Jones protein, beta2microglobulin, LDH, albumin), anti-MAG titer 
every 3 months during the first year then every 6 months till month +54; Pregnancy test in 
childbearing potential at baseline, before 48 before of the first dose and then every 4 weeks till 8 
weeks after the last dose of zanubrutinib, is needed. 
● Neurological scales at baseline, every 6 months till months +24 and after for responding patients: 
MRC sum score, INCAT disability and INCAT sensory sum scores (ISS), Overall Neuropathy 
Limitations Scale (ONLS), I-RODS functional score, 10-meter walking time, 9-hole peg test, NRS; 
● Bone marrow biopsy performed at baseline or within the last 3 months from study entry, after 24 and 
48 months of zanubrutinib; 
● Bone marrow aspirate at baseline, after 24 and 48 months of treatment; 
● Abdomen US, Heart ultrasound and Electrocardiogram (ECG) at baseline, after 24 and 48 months. 
● Plasma MYD88 L265P cell-free DNA at baseline and every 6 months till month +54; 
● Quality of life will be assessed by FACT-GOG-NTX-13 QOL questionnaire every 3 months during the 
first year and then every 6 months. 
 
 
Schedule of Activities 
 
 
Screening 
Months of treatment 
Treatment cycles 
(28-day cycle) 
- 
+1 
+3 
+6 
+9 
+12 
+18 
+24 
+30 
+36 
+42 
+48 
+54 
Visit days +/- 7  
-28 to -1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion / 
exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
phase 
(28 
day) - Baseline 
CBC and biochemistry 
ENG/EMG 
Hearth US, EKG 
anti-MAG antibody titer 
abdomen US 
bone marrow biopsy and 
aspirate 
cfDNA 
QoL, neurological 
assessment, pregnancy test
Start of therapy                                                                          End of therapy 
Response 
 assessment 
 
 
Zanubrutinib 
Zanubrutinib 
+3 +6 +9 +12 
+18 
+24 
+30 
+36 
+42 
+48 
+54 
months of therapy 
 

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Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropathy 
diagnosis 
and 
treatment history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Blood exams3 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ENG/EMG1 
x 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Nerve ultrasound2 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
Neurological 
exams4 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Abdomen 
and 
heart US, ECG6 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
Bone 
marrow 
biopsy 
and 
aspirate5 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
cfDNA7 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Quality of life  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Response 
assessment8 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
1. 
electroneurography (ENG)/electromyography (EMG) at upper and lower limbs at baseline and then every 6 months till month 
+54; 
2. 
Nerve ultrasound at upper and lower limbs at baseline, after 24 and 48 months of zanubrutinib, when available; 
3. 
Complete blood count with differential, biochemistry (hepatic and liver function, serum protein electrophoresis, IgG, IgA, IgM, 
free light chains, 24h-urine protein, Bence Jones protein, beta2microglobulin, LDH, albumin), anti-MAG titer every 3 months 
during the first year then every 6 months till month +54; Pregnancy test in childbearing potential at baseline, before 48 before of 
the first dose and then every 4 weeks till 8 weeks after the last dose of zanubrutinib, is needed. 
4. 
Neurological scales at baseline, every 6 months till months +24 and after for responding patients: MRC sum score, INCAT 
disability and INCAT sensory sum scores (ISS), Overall Neuropathy Limitations Scale (ONLS), I-RODS functional score, 10-meter 
walking time, 9-hole peg test, NRS; 
5. 
Bone marrow biopsy performed at baseline or within the last 3 months from study entry, after 24 and 48 months of 
zanubrutinib. Bone marrow aspirate at baseline, after 24 and 48 months of treatment; 
6. 
Abdomen US, Heart ultrasound and Electrocardiogram (ECG) at baseline, after 24 and 48 months.  
7. 
Plasma MYD88 L265P cell-free DNA at baseline and every 6 months till month +54; 
8. 
Quality of life will be assessed by FACT-GOG-NTX-13 QOL questionnaire every 3 months during the first year and then every 6 
months. 
 
6 Risks and benefits assessment 
The therapeutic approach of the present study may be beneficial for patients with anti-MAG antibody 
neuropathy in terms of efficacy in comparison with an acceptable toxicity profile. 
 
Risks to participating in the study 
- Toxicity 
Please refer to Appendix C: study drug toxicities. 
 
- Psychosocial distress 
Trial participation can entail psychological distress for patients beyond that caused by the illness 
itself: patients may experience depression, stress, uncertainty as a result of trial participation, 
loneliness and fear. Trial participation can also be a social burden for patients, straining on 
relationships with partners and on other social contacts. 
 
7 Treatment 
Patients with WM, MZL and CLL  will be treated with zanubrutinib according to the Italian drug 
agency (AIFA) reimbursement criteria, while zanubrutinib will be provided by the sponsor for 
patients with MGUS or other low-grade lymphoproliferative diseases . All patients will receive 
zanubrutinib at 160mg bis-in-die orally or 320mg QD from day 1 of the first cycle for at least 2 years 

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and, if the patients have at least a stabilization of the disease, they will be treated for additional 2 
years. After 4 years all patients will stop treatment. Therefore, although the treatment authorization 
differs, the conduct of the study does not differ, continuation of zanubrutinib for an additional two 
years is governed by the same predefined neurological response criteria. This ensures that treatment 
exposure, decision-making processes, and endpoints remain consistent across the study population. 
Both groups will be analyzed together for endpoints, given the identical assessment schedule, 
outcome measures, and longitudinal data collection 
 
 
Drugs management 
Zanubrutinib bottles will be stored at room temperature 15ºC to 30ºC (59°F to 86°F). Zanubrutinib 
will be administered as two 80-mg capsules by mouth twice a day (160 mg twice a day) with or 
without food. Patients will take zanubrutinib with water at approximately the same time every day, 
with a minimum of 8 hours between consecutive doses. Zanubrutinib capsules should not be opened, 
broken, or chewed at any time. Patients should be instructed that if a dose of zanubrutinib is not 
taken at the scheduled time, they should skip the study drug if the time to next dose is 8 hours or 
less,and return to normal dosing with the next dose. If a patient vomits after taking the zanubrutinib 
capsules, that dose should not be repeated. 
 
Dose reductions and management and prophylaxis of Specific Adverse Events  
 
Table 1. Guidelines for Management of Specific Adverse Events 
HEMATOLOGIC TOXICITY 
Grade 3 or 4 neutropenia 
with/without fever and 
infection despite G-CSF 
Hold zanubrutinib 
Administer G-CSF or growth factors for neutropenia as indicated 
When counts recover to ANC ≥ 1.5 × 109/L and/or platelets 
are ≥ 75 × 109/L resume treatment, and all signs of active infection are 
resolved (see next Section for the next dose). 
Any grade intracranial 
hemorrhage 
Discontinue zanubrutinib permanently 
Severe thrombocytopenia, 
(platelets < 25 000/μL) 
and/or or presence of 
symptomatic bleeding 
Hold treatment with zanubrutinib for severe thrombocytopenia (platelets < 
25,000/μL) or presence of symptomatic bleeding until resolution of 
bleeding 
Platelets may be transfused at the discretion of the investigator 
 
HEMATOLOGIC TOXICITY 
Grade 3 or 4 
neutropenia 
with/without fever and 
infection despite G-CSF 
Hold zanubrutinib 
Administer G-CSF or growth factors for neutropenia as indicated 
When counts recover to ANC ≥ 1.5 × 109/L and/or platelets 
are ≥ 75 × 109/L resume treatment, and all signs of active infection are 
resolved (see next Section for the next dose). 
 
 

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Severe 
thrombocytopenia, 
(platelets < 25 000/μL) 
and/or or presence of 
symptomatic bleeding 
 
 
 
Hold treatment with zanubrutinib for severe thrombocytopenia 
(platelets < 25,000/μL) or presence of symptomatic bleeding until 
resolution of bleeding 
Platelets may be transfused at the discretion of the investigator 
 
 
 
 
 
 
 
 
 
In presence of any grade intracranial hemorrhage permanently discontinue 
zanubrutinib. 
When bleeding is resolved to grade 1, platelet level rises up to 50,000/μL 
without transfusion support for 5 consecutive days zanubrutinib at dose 
level (-1) 
If underlying condition cannot be treated to full resolution, permanently 
discontinue zanubrutinib. 
OTHER TOXICITIES 
Atrial fibrillation (AF) 
Hold until AF is controlled and anticoagulation introduced if required 
Re-start at either the original dose or dose level (-1), at the discretion of the 
treating investigator. 
Inadequately controlled 
hypertension 
Hold until hypertension to less than or equal to baseline. If baseline is 
greater than grade 1; hold until less than or equal to Grade 1 if BL is less 
than or equal to Grade 1. Re-start at the original dose level. If same event 
recurs at ≥ Grade 3, reduce dose by one level after recovery to BL or Grade 
1. 
Grade 3 or 4 non-hematologic 
events not specifically 
described above 
Delay treatment with zanubrutinib for a maximum of 56 days. 
First event: if improvement to Grade ≤ 1 or baseline, resume treatment at 
the same dose 
For subsequent events: if improvement to Grade ≤ 1 or baseline, restart 
treatment at one dose level reduction. 
Grade 1-2 non-
hematologic toxicity 
No dose reduction or delay.Delay treatment (zanubrutinib) for a maximum 
of 56 days until resolution to Grade ≤ 1 (or baseline status) 
After resolution, resume full dose of treatment 
Grade 1 non-hematologic 
Toxicity 
No dose reduction or delay. 
G-CSF = granulocyte stimulating factor. 
 
Zanubrutinib dose after treatment discontinuation 
Treatment with zanubrutinib may be restarted upon resolution of toxicity and per investigator discretion 
if held for a maximum of 56 consecutive days. 
If, in the investigator’s opinion, it is in the patient’s best interest to restart treatment after > 56 
days, then written approval must be obtained from the sponsor’s. 
 
1) First treatment interruption: once the toxicity has resolved to grade 1 or baseline level, 

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therapy with zanubrutinib may be restarted at the same dose. 
 
2) If the toxicity recurs, and for any subsequent occurrences, the dose of zanubrutinib should 
be reduced (Table 3). Based on patients’ clinical characteristics, higher dose reduction may be 
considered at the discretion of the investigator. 
 
Table 2. Zanubrutinib dose after treatment discontinuation 
Toxicity 
occurrence 
Zanubrutinib 
Prior dose of 
zanubrutinib at 
interruption 
Restart 
zanubrutinib 
First 
160 mg twice daily 
Restart at 160 mg 
twice daily* 
 
Second 
160 mg twice daily 
Restart at 80 mg 
twice daily 
Third 
80 mg twice daily 
Restart at 80 mg 
once daily 
Fourth 
80 mg once daily 
Discontinue 
zanubrutinib 
*In patients with prior severe bleeding, re-start zanubrutinib at dose level (-1) 
 
If the underlying condition cannot be treated to full resolution, permanently discontinue 
zanubrutinib. Dose modifications for hematological toxicity in patients with WM/CLL/MZL must 
consider the increased frequency of hematological compromise at the initiation of therapy. 
Therefore, the standard criteria used for solid tumors are difficult to be applied directly; many 
patients would be considered to have Grade II to IV hematological toxicity at baseline. The underlying 
disease, as well as adverse reactions to the therapy under study may further worse these cytopenias. 
 
Concomitant surgery procedures, drugs and              
Foods Surgery and Procedures 
Susceptibility to bleeding has been observed with BTK inhibitors. Treatment with zanubrutinib should 
be held for 3 to 7 days before and after surgery, depending upon the type of surgery and the risk of 
bleeding. 
 
Infection prophylaxis 
Patients treated with BTK inhibitors such as zanubrutinib have an increased risk of Pneumocystis 
Carinii, also with atypical phenotype, fatal and non-fatal bacterial infections, but also herpes viral, 
cryptococcal, aspergillus infections and hepatitis B virus (HBV) reactivation. Therefore, prophylaxis 
with Bactrim is recommended. The use of azoles as anti-fungal prophylaxis or therapy should be 
discussed because of the potential drug−drug interactions. Immunoglobulins should be considered 
when clinically indicated in patients with hypogammaglobulinemia. Prophylactic antiviral therapy 
with lamivudine or entecavir or HBV-DNA monitoring (every 3 months), is recommended in patients 
with negative HBsAg and HBV-DNA but positive HBcAb (regardless of HBsAb status). 
 
Prophylaxis of neutropenia 
Use of neutrophil growth factors is permitted per the ASCO guidelines. 
 
Live viral vaccines 
Live viral vaccines to patients should not be administered. The safety of immunization with 
vaccines following zanubrutinib therapy has not been studied. 
 
Skin cancer 

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Since, the most frequent second primary malignancy associated with the use of zanubrutinib in 
patients with B-cell malignancies was skin cancer (basal cell carcinoma and squamous cell 
carcinoma of skin). Patients should be advised to use sun protection. 
 
Prohibited Food 
Use of the following foods is prohibited during study treatment and for at least 3 days prior to 
initiation of study treatment: 
• Grapefruit 
• Grapefruit products 
• Seville oranges (including marmalade containing Seville oranges) 
• Star fruits 
 
Drugs not allowed during the study 
The use of warfarin and other vitamin K antagonists is not allowed during this study. The investigator 
should evaluate the use of other anticoagulation therapies, such as apixaban/dabigatran or low- 
molecular weight heparin. Steroid therapy for anti-neoplastic intent with the exception of inhaled 
steroids for asthma, topical steroids, or replacement/stress corticosteroids are allowed only for 10 
days during the study at any time. 
 
Drug−Drug Interaction 
It has been shown that co-administration of zanubrutinib with the strong CYP3A inducer rifampin 
decreased AUC0-∞ of zanubrutinib by 13.5-fold in healthy subjects. Co-administration of 
zanubrutinib with strong CYP3A inhibitor itraconazole increased AUC0-∞ of zanubrutinib by 3.8-
fold (refer to Section 1.3.2.3). These results are consistent with the role for CYP3A isoenzymes as the 
principal 
metabolic 
pathway 
for 
zanubrutinib. 
Administration 
of 
zanubrutinib 
with 
strong/moderate CYP3A inhibitors or CYP3A inducers (see Table 5 for a list of these medications) 
and grapefruit juice and Seville oranges should be used with caution as they may affect the 
metabolism of zanubrutinib (APPENDIX D). If possible, patients are encouraged not to use 
strong/moderate CYP3A inhibitors and inducers and should consider using alternative agents. If 
these agents will be used, follow the dose modification table in Table 8. The medical monitor should 
be consulted in these situations. Please refer to http://medicine.iupui.edu/clinpharm/ddis/main-
table/ for a more complete list. 
Table 3. Dose Modification for zanubrutinib when Co-Administered with Strong/Moderate 
CYP3A Inhibitors or Inducers 
 
CYP3A 
Co-administered Drug 
Recommended use 
Inhibition 
Strong CYP3A inhibitor (eg. ketoconazole, 
conivaptan, 
clarithromycin, 
indinavir, 
itraconazole, 
lopinavir, 
ritonavir, 
telaprevir, posaconazole, voriconazole) 
80 mg once daily 
Moderate 
CYP3A 
inhibitor 
(eg. 
erythromycin, ciprofloxacin, diltiazem, 
dronedarone, 
fluconazole, 
verapamil, 
aprepitant, imatinib, grapefruit products) 
80 mg twice daily 
Induction 
Strong CYP3A inducer (e.g. carbamazepine, 
phenytoin, rifampin, St. 
John’s wort) 
Avoid concomitant use; Consider alternative 
agents with less induction 
potential. 

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Moderate CYP3A inducer (eg. bosentan, 
efavirenz, etravirine,  
modafinil, nafcillin) 
160 mg twice daily, use with caution; 
Monitor for potential lack of efficacy. 
 
8 Pregnancy and contraception 
Adult subjects of childbearing potential (ACBP) must: 
•  
Understand the potential teratogenic risk to the unborn child and the need for effective 
contraception. 
• Be capable of complying with effective contraceptive measures. 
•  
Be informed and understand the potential consequences of pregnancy and the need to 
notify her study doctor immediately if there is a risk of pregnancy. 
•  
Understand the need to commence the study treatment as soon as study drug is 
dispensed following a negative pregnancy test. 
•  
Understand the need and accept to undergo pregnancy testing based on the frequency 
outlined in this protocol. 
ACBP enrolled in this protocol must agree to use two reliable forms of contraception simultaneously 
or to practice complete abstinence from heterosexual contact during the following time periods 
related to this study: 1) while participating in the study; 2) in case of dose interruptions; and 3) after 
the last dose of study drug. 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. ACBP must be referred to a qualified provider of contraceptive 
methods if needed. The following are examples of highly effective and additional effective methods 
of contraception 
Highly effective methods: 
● Hormonal (birth control pills, injections, implants) 
● Tubal ligation 
● Partner’s vasectomy. 
 
Additional effective methods: 
● Male condom 
● Diaphragm (not recommended in patients with low platelets count) 
● Cervical cap. 
 
Pregnancy tests 
Pre-menopausal women who are not surgically sterile must agree to have pregnancy tests: 
1. One serum test at baseline 
2. One serum test within 48 hours prior treatment with zanubrutinib start 
3. One serum test every 4 weeks during treatment period with zanubrutinib combination. 
4. After zanubrutinib discontinuation: 
a) one serum test after 4 and 8 weeks from the last dose. 
 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a 
postmenopausal state (>/= 12 continuous months of amenorrhea with no identified cause other than 
menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator (e.g., Mullerian agenesis). The 
definition of childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
The reliability of sexual abstinence should be evaluated in relation duration of the clinical trial and 
the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. Willingness to not donate sperm or oocytes during the entire study treatment period 

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and after treatment discontinuation for 90 days after the last dose of zanubrutinib. 
 
9 Duration of the study 
Definition of the ending of the study: the last visit of the last subject in the last clinical trial site 
involved in the study. 
Estimated starting date: Q4 2025 
Ending date: Q1 2031 
Recruitment duration: 18 months 
 
10 Discontinuation of study treatment  
Completion 
A subject will be considered to have completed the study if he or she has not died before the end of 
the study, has not been lost to follow-up, or has not withdrawn consent before the end of study. 
 
Discontinuation of treatment 
Treatment should be discontinued if any of the following occurs: 
● 
The subject experiences disease progression or relapse 
● 
The subject becomes pregnant 
● 
The subject refuses further treatment with the study drug 
● 
The investigator believes that for safety reasons (e.g. AE) it is in the best interest of the subject 
to stop treatment. 
● 
Any grade intracranial hemorrhage;  
● 
Any toxicity recurs 4 times 
● 
In case a toxicity cannot be treated to resolution; 
 
Withdrawal from the study 
A subject will be withdrawn from the study for any of the following reasons: 
1. 
Withdrawal of consent 
2. 
Lost to follow-up 
3. 
Death 
4. 
The sponsor discontinues the study for one of the following reasons: 
a. 
Evidence of lack of therapeutic effect or disease progression 
b. 
Toxicity and/or any SAEs that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
c. 
Major violation of the study protocol. 
 
If a subject is lost to the follow-up, then every reasonable effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal. The 
measures taken up must be documented. When a subject withdraws before completing the study, 
the reason for the withdrawal is to be documented in the CRF and in the source document. Study 
drug assigned to the withdrawn subject may not be assigned to another subject. Subjects who 
withdraw will not be replaced. 
 
10.1 Study Discontinuation Criteria 
In accordance with ICH E6(R3) Good Clinical Practice and Regulation (EU) 536/2014, the Sponsor may 
temporarily halt or permanently discontinue the clinical trial if new information arises that results in an 
unfavourable risk–benefit assessment or compromises participant safety, trial integrity, or regulatory 

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compliance. 
The clinical trial may be discontinued under any of the following circumstances (non-exhaustive list): 
• 
Identification of unacceptable risks to participants, including adverse events or reactions whose 
nature, severity, or frequency is new, unexpected, or inconsistent with the known safety profile of the 
investigational medicinal product. 
• 
Emergence of relevant toxicity or other safety concerns that cannot be adequately managed 
within the framework of the study and that modify the risk–benefit balance. 
• 
Receipt of new safety information from other clinical trials, non-clinical studies, pharmacovigilance 
activities, or post-marketing data indicating potential harm or a negative change in the risk–benefit 
profile. 
• 
A recommendation from Regulatory Authorities and Ethics Committees to suspend or terminate 
the study for safety, ethical, or scientific reasons. 
• 
Major non-compliance with the protocol, ICH GCP, or applicable regulatory requirements that may 
compromise participant protection or the scientific value of the trial. 
• 
Any other situation that, in the judgement of the Sponsor, renders continuation of the study 
unjustifiable, unsafe, or non-compliant with the applicable regulatory framework. 
• 
If the study is temporarily halted or permanently discontinued, the Sponsor will fulfil all obligations 
established by Regulation (EU) 536/2014, including timely notification to the Member States 
concerned via CTIS, the relevant Ethics Committee(s), and all investigators. The Sponsor will ensure 
that all trial participants are appropriately informed and managed in accordance with ethical 
standards and regulatory requirements. 
11 Drug supply Accountability 
Zanubrutinib for WM, MZL and CLL will be used according to the Italian drug agency, while for MGUS 
or other low-grade lymphomas will be supplied by the Sponsor. 
 
The investigator and the trial site are responsible for investigational product accountability. To this 
end, it is assumed that all clinical trial supplies will be delivered to and by the responsibility of a 
suitably qualified and authorized person such as a hospital pharmacist, who will document drug 
disposition and accountability for the duration of the trial. 
 
Packaging, labelling and storage 
Packaging and labelling will be in accordance with Good Manufacturing Practice (GMP) for clinical 
trials. They must not be employed for any other trial or for any other clinical use. 
 
Drug reconciliation procedures 
The drug formulation, dose, number of bottles/capsules dispensed, received, and returned must be 
recorded. The investigator must maintain an accurate record of the shipment and dispensing of the 
study drugs in a drug accountability ledger, a copy of which must be given to the Sponsor at the end 
of the study. An accurate record of the date and amount of study drug dispensed to each patient must 
be available for inspection at any time. All drug supplies are to be used only for this protocol and not 
for any other purpose. The investigator must not destroy any drug labels, or any partly used or 
unused drug supply. At the conclusion of the study, and, as appropriate during the course of the 
study, each local site will destroy all used and unused drug containers by providing to the Sponsor 
with a certificate of destruction. 
 

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12 Criteria of evaluation of response 
Efficacy evaluations will be performed as specified in the Time and Events Schedule and will include the 
following examinations: 
● Neurological improvement is defined by an improvement of at least 1 point in 2 different 
neurological scales such as a decrease for the ONLS, INCAT disability, INCAT sensory sum scores 
(ISS), but an increase of MRC sum and I-RODS functional score; 
● Neurophysiology, EMG/ENG and nerve ultrasound (where available) 
● Disease-related symptoms, physical examination and patient-reported outcome and quality of life. 
● Physical examinations will focus on examination of lymph nodes, liver and spleen. 
● CBC with measurement of data including absolute lymphocyte count hemoglobin, platelet, 
monoclonal protein, IgM levels, anti-MAG antibody titer. 
● Overall response rate (ORR), defined as the proportion of subjects with measurable disease 
achieving a best overall response of either complete remission (CR), very good partial response 
(VGPR) and partial response (PR). 
 
Efficacy Outcome Measures 
● Disease relapse will be defined by as worsening of at least 1 point in 2 different neurological scales 
such as increase of ONLS, INCAT disability, INCAT sensory sum scores (ISS), but a decrease of MRC 
sum score, I-RODS functional score after the nadir; 
● ORR (defined as rate of a clinical response of CR, VGPR or PR) after 12, 24 and 48 months  
 
of zanubrutinib treatment 
● Plasma cell free DNA 
 
Neurophysiology recommendation 
 
Neurophysiological examination is assessed at baseline, and every 6 months for 24 months. For 
responding or stabilized patients, continuing receiving zanubrutinib, EMG/ENG is continued till 
month +54. Other assessments take place if clinically necessary. 
Neurophysiological 
evaluation 
is 
performed, 
using 
a 
standard 
proper 
machine. 
For 
electroneurographic (ENG) study a standard method with surface electrodes for stimulation and 
recording, a stimulus duration of 0,1 ms, and a signal bandwidth 20 Hz-10 kHz are used. The 
following nerves are studied: median nerve, by recording from abductor pollicis brevis muscle and 
from index finger; ulnar nerve, by recording from abductor digiti minimi muscle and little finger; 
radial nerve, by recording from skin over the extensor tendons to the thumb; peroneal nerve, by 
recording from extensor digitorum brevis muscle; tibial nerve, by recording from abductor hallucis 
brevis muscle; sural nerves, by recording posterior to the lateral malleolus; superficial peroneal 
nerve, by recording between the tibialis anterior tendon and lateral malleolus. Ulnar and tibial nerve 
F wave latency is included in the electrodiagnostic evaluation. ENG parameters analyzed are: distal 
motor latency (DML), compound action muscle potential (CMAP) amplitude, negative peak duration 
of distal CMAP, motor conduction velocity (MCV), sensory nerve action potential (SNAP) amplitude 
and sensory conduction velocity (SCV). Distance between the distal stimulation site and the 
recording motor site is measured in order to ensure correct interpretation of DML change during 
follow up and to obtain the Terminal Latency Index (TLI) [(distance between distal stimulus site and 
the recording surface) / (MCV × DML)]. 
Electromyography with a coaxial needle electrode was performed recording spontaneous and 
voluntary activity from some muscles of upper and lower limb (at least from first dorsal interosseus, 
biceps brachii, vastus medialis, tibialis anterior and gastrocnemius), to evaluate axonal damage. 
 
Evaluation of toxicity Safety Outcome Measures 
Data from all subjects who receive zanubrutinib will be included in the safety analyses. Subjects who 
entered the study and did not take zanubrutinib and had this confirmed, will not be evaluated for 
safety. The severity of the toxicities will be graded according to the NCI CTCAE v5.0. 

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The safety outcome measures for this study are as follows: 
• Nature, frequency, and severity of adverse events and serious adverse events 
• Changes in vital signs, physical findings, and clinical laboratory results during and following study 
treatment 
• Premature withdrawals 
 
Time to event analysis 
Event free survival will be calculated as time from the start of therapy to relapse or death or start of 
a new therapy (event) or last known follow-up (censured), whichever is first reported. Patients still 
alive without signs of worsening of neurological symptoms nor new treatment will be censored on 
the last date a subject is known to be alive or lost to follow-up.  Time to relapse progression will be 
calculated as time from the start of therapy to the worsening of neurological symptoms defined as 
worsening of least 1 point in at least 2 neurological scales such as Overall Neuropathy Limitations 
Scale (ONLS), INCAT disability, INCAT sensory sum scores (ISS), MRC sum score, I-RODS functional 
score after the nadir. Overall survival (OS) will be calculated as time from the start of therapy to 
death (event) or last known follow-up (censured). Survival time of living subjects will be censored 
on the last date a subject is known to be alive or lost to follow-up. 
 
13  Statistical considerations 
Size of study population s. 
The reference population derives from the II phase NCT00050245 trial which has been published 
in Annals of Neurology 2009;65:286-293. Twenty-six patients with antiMAG neuropathy were 
randomized to four weekly infusions of 375mg/m2 rituximab or placebo. The primary endpoint 
was an increase of at least 1 point of the INCAT leg disability scores at month 8. Thirteen patients 
were randomized to rituximab and 13 to placebo. Randomization was balanced for age, 
electrophysiology, disease duration, disability scores, and baseline B cells. After 8 months, by 
intention to treat, 4 of 13 rituximab-treated patients improved by 1 INCAT score compared with 0 
of 13 patients taking placebo (p=0.096). However, excluding 1 rituximab-randomized patient who 
had normal INCAT score at entry, and thus could not improve, the results were significant (p= 
0.036). The time to 10m walk was significantly reduced in the rituximab group (p=0.042) (intention 
to treat). Clinically, walking improved in 7 of 13 rituximab-treated patients. 
Considering the refenreced proportion p0≈0.323,  a one-sided z test for one-sample proportion, a 
level of significance (α) of 5%, a power of the study (1-β) equal to 80%, and assuming that the 
proportion of patients with improvement of at least 1 point in 2 neurological scales (INCAT or ISS 
or ONLS or I-RODS or MRC) after 12 months of zanubrutinib is 50% (p1=0.50), the number of 
patients needed to be studied is 45 (https://www.trialdesign.org/). Hypothesizing a study 
withdrawal of 5% the number of patients to enroll should be at least 47 patients. We plan to screen 
50 patients from 9 medical centers.  
 
Efficacy Analysis Populations 
The All-Subjects-as-Treated (ASaT) population, which consists of all enrolled subjects who receive 
at least one dose of study medication, will serve as the primary population for the analyses of efficacy 
data in this trial. Details on the approach to handling missing data for efficacy analyses are provided 
in Statistical method section. Only screen failures and patients who refuse before the treatment start 
would be excluded from the statistical analysis. 
 
Safety Analysis Populations 
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data. At least 
one laboratory or vital sign measurement obtained subsequent to at least one dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess change 
from baseline, a baseline measurement is also required. 
 

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     Statistical methods  
  
Efficacy results that will be considered to be statistically significant after consideration of the 
strategy for controlling the Type I error are described in Sample Size Section. 
 
The primary endpoint will be summarized by the observed proportion and associated confidence 
intervals. The one-sided 95% lower confidence bound will be used for the primary hypothesis test 
(reject H0 if the lower bound exceeds p0). Two-sided 95% intervals will be reported for descriptive 
purposes. 
Secondary endpoints will be analyzed descriptively and inferentially according to their 
measurement scale. The proportions of patients with neurological improvement at 24 and 48 
months and the proportions achieving ENG/EMG improvement at 12, 24 and 48 months will be 
summarized with the observed proportion and 95% confidence intervals. Continuous laboratory 
markers (monoclonal protein, IgM, and anti-MAG antibody titers) will be summarized at each 
timepoint and 95% CIs and analyzed using Wilcoxon or students’ t test. Adverse events, serious 
adverse events and adverse events of special interest will be presented by type, frequency and 
severity in the safety population. Overall response rate (CR, CRi, VGPR, PR) will be reported as 
proportions with 95% CIs, and duration- and time-to-response will be described using Kaplan–Meier 
methods. Event-free survival, time to progression, and overall survival will be analyzed using 
Kaplan–Meier estimators with medians and 95% CIs. 
Key efficacy analyses for primary and secondary endpoints in this study have been summarized 
 

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The baseline characteristics, hematological and neurological responses will be compared according 
to the MYD88 mutation (present vs wild-type), MGUS vs overt lymphoma with the Wilcoxon or 
students’ t test, Fisher exact test, Chi-square test when appropriated. Survival curves will be plotted 
with Kaplan-Meier methods and compared with Log-rank test in univariable analysis and by means 
of Cox regression m\odel in multivariable analysis, after assessment of proportionality of hazards. 
Comparison between the primary endpoint with the historical control will be based on a one-sided 

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5% test level. All the other tests will be 2-sided, accepting p<0.05 as indicating a statistically 
significant difference and confidence intervals will be calculated at 95% level. The number and 
percentage of subjects screened, treated, primary reasons for screening failure, and discontinuation 
will be displayed.  
All analysis will be performed using R software (R: A language and environment for statistical 
computing. R Foundation for Statistical Computing, Vienna, Austria). 
 
The study is powered as a one-sample one-sided test of proportion vs historical control (α = 0.05 
one-sided, power = 80%). We assume the true responder proportion with zanubrutinib p1=0.50 
and a historical control responder proportion p0≈0.323 (source: Dalakas et al., Ann Neurol 
2009;65:286-293), which yields an approximate required sample size of 45 evaluable patients 
using the standard normal approximation for proportions. Allowing for a 5% non-
evaluable/withdrawal rate increases planned enrolment to 47 patients; therefore we plan to screen 
up to 50 patients at 9 clinical centers.  
Sample-size calculations were performed with the formula 
 
and confirmed by [trialdesign.org]. 
 
 
Statistical Methods for Safety Analyses 
All adverse events (AEs) will be tabulated, safety and tolerability will be assessed by clinical review 
of all relevant parameters including adverse experiences, laboratory tests, and vital signs within drug 
cohort and total. Summary statistics (counts, percentage, mean, standard deviation, etc.) will be 
provided for the safety endpoint as appropriate. The incidence rate of Grade 3 or higher adverse 
events and the incidence rate of Grade 5 AEs will be provided as appropriate. 
 
Interim analysis 
No formal interim analysis will be performed. However, a safety assessment will be made in the first 
20 enrolled patients by the study coordinator and co-coordinators. Toxicity will be considere 
unacceptable if 25% or more patients discontinue treatment permanently due to an AE. 
14 Independent data monitoring committee 
No independent clinical data monitoring committee has been appointed for this study. 
 
15 Quality of life assessment 
FACT-GOG-NTX-13 QOL questionnaire every 3 months during the first year and then every 6 
months (https://www.facit.org/measures/FACT-GOG-NTX-13). 
 
16 Translational research Rationale 
A relevant number of patients with anti-MAG neuropathy harbor MYD88L265P mutation, being 
present in almost all patients with associated Waldenstrom macroglobulinemia and less common in 
patients with MGUS. MYD88L265P mutation is rare in patients with CLL or MZL. 
Objective 
To define the biologic characteristics of patients with anti-MAG neuropathy cells in terms of 
MYD88L265P and CXCR4Whim-like mutations. 
Samples collection and schedule 
Peripheral blood samples will be collected at baseline and every 6 months (Appendix E).  
Methods 
gDNA extraction from WBC cells and cfDNA extraction from plasma will be performed according to 
the manufacturer by Maxwell® RSC Blood DNA and by Maxwell® RSC LV ccfDNA kit, respectively. 
MYD88 (L265P) mutation levels will be assessed by a custom dual labelled MYD88 (L265P) probe 
assay, designed for ddPCR and validated by the OUT, on gDNA extracted from BM and on cfDNA 

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extracted from plasma as previously reported25. ddPCR will be performed on QX200 system (Bio-
Rad). MYD88 (L265P) ddPCR cut-off is settled based on the background level defined from a group 
of control samples including samples from multiple myeloma patients and the healthy samples. 
Furthermore, similar ddPCR approaches will be used for CXCR4 from bone marrow samples. 
 
17 List of recruiting Italian centers 
See attached file  “Elenco centri partecipanti_studio Mazinga_v1.0 del 10/07/2025” 
 
18 Adverse Events Definition 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product. and which does not necessarily have a causal relationship with this treatment 
[Dir 2001/20/EC Art 2(m)]. An adverse event can therefore be any unfavorable and unintended sign 
(e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product (GVP Annex IV, ICH-
E2D Guideline). This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities (GVP Annex 1 – European directive 2001/20/EC). 
 
Adverse Reaction 
An adverse reaction is defined as a response to a medicinal product which is noxious and unintended. 
[DIR 2001/83/EC Art 1(11)]. Response in this context means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, ie, the relationship cannot be ruled 
out. (Annex IV, ICH-E2A Guideline). Adverse reactions may arise from use of the product within or 
outside the terms of the marketing authorization or from occupational exposure (European directive 
2001/83/EC Art 101(1)). Conditions of use outside the marketing authorization include off-label 
use, overdose, misuse, abuse and medication errors. 
 
Serious Adverse Event or Serious Adverse Reaction 
A serious AE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose: 
● 
Results in death 
● 
Is life-threatening (the subject was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.) 
● 
Requires inpatient hospitalization or prolongation of existing hospitalization 
● 
Results in persistent or significant disability/incapacity 
● 
Is a congenital anomaly/birth defect 
● 
Is a suspected transmission of any infectious agent via a medicinal product 
● 
Is Medically Important* 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is also 
appropriate in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should usually 
be considered serious. 
For reports of hospitalization, it is the sign, symptom or diagnosis, which led to hospitalization that 
is the serious event for which details must be provided. Any event requiring hospitalization (or 
prolongation of hospitalization) that occurs during the course of a subject's participation in a study 
must be reported as a serious adverse event, except hospitalizations for the following: 
• hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such as 
pending placement in long-term care facility). 
• surgery or procedure planned before entry into the study (must be documented in the CRF). Note: 
Hospitalizations that were planned before the signing of the ICF, and where the underlying condition 
for which the hospitalization was planned has not worsened, will not be considered serious adverse 

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events. Any adverse event that results in a prolongation of the originally planned hospitalization is 
to be reported as a new serious adverse event. 
• disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of efficacy 
will be reported if they fulfill the serious adverse event definition. 
• a standard procedure for protocol therapy administration will not be reported as a serious adverse 
event. Hospitalization or prolonged hospitalization for a complication of therapy administration will 
be reported as a serious adverse event. 
• the administration of blood or platelet transfusion. Hospitalization or prolonged hospitalization for 
a complication of such transfusion remains a reportable serious adverse event. 
• a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, sampling 
for laboratory tests, bone marrow sampling, pharmacokinetic or biomarker blood sampling). 
Hospitalization or prolonged hospitalization for a complication of such procedures remains a 
reportable serious adverse event. 
• prolonged hospitalization for technical, practical, or social reasons in the absence of an adverse 
event. 
 
Unlisted (Unexpected) AE/Reference Safety Information 
An AE is considered unlisted if the nature or severity is not consistent with the applicable product 
reference safety information. 
 
Causality of adverse event 
The Investigator(s) must determine the relationship between the administration of study drug and 
the occurrence of an AE/SAE. An adverse event is considered not associated with the use of the 
treatment if the attribution is not related or doubtful according to the definitions listed below: 
Not Related: an AE that is not related to the use of the drug. 
Doubtful: an AE for which an alternative explanation is more likely, e.g., concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
An adverse event is considered associated with the use of the treatment if the attribution is possible, 
probable, or definitely according to the definitions listed below: 
Possible: an AE that might be due to the use of the drug. An alternative explanation, e.g., concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded. 
Probable: an AE that might be due to the use of the drug. The relationship in time is suggestive (e.g., 
confirmed by dechallenge). An alternative explanation is less likely, e.g., concomitant drug(s), 
concomitant disease(s). 
Very Likely: an AE that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 
 
Classification of severity of adverse event 
For both AE and SAE, the investigator(s) must assess the severity of the event. 
The severity of adverse events (AE) will be graded on a scale of 1 to 5 according to the Common 
Terminology Criteria for Adverse Events v 5 (CTCAE): 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Ref
ere nce_5x7.pdf. 
 
If a specific event is not included in the NCI CTCAE toxicity scale, the following scale should be 
used to grade the event: 
Grade 
Definition 
1 
Mild Awareness of sign, symptom, or event, usually transient, requiring no special 
treatment and generally not interfering with usual daily activities 

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2 
Moderate Discomfort that causes interference with usual activities; usually ameliorated by 
basic therapeutic manoeuvres 
3 
Severe is Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
Activities of Daily Living. 
4 
Life-threatening Immediate risk of death; requires hospitalization and clinical 
intervention. 
5 
Death 
 
Reporting Procedures 
Adverse Event 
All AEs, whether serious or non-serious and pregnancy exposures and/or pregnancy in partners, will 
be recorded by the physician from the time the patient signs the informed consent for study 
participation until a minimum of up to 6 months after the last dose or to the end of the follow-up 
period whichever is longer. 
If a subject starts other therapies, then SAEs will no longer be required to be reported. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, must 
be recorded using medical terminology in the source document and the CRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (e.g., cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). 
Investigators must record in the CRF their opinion concerning the relationship of the adverse event 
to study therapy. The causality will be assessed for each study drug separately. A persistent adverse 
event is one that extends continuously, without resolution, between patient evaluation timepoints. 
Such events should be recorded only once on the Adverse Event eCRF. The initial severity (intensity 
or grade) of the event will be recorded at the time the event is first reported. If a persistent adverse 
event becomes more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF. If the event becomes serious, it should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning that the event became serious). The Adverse Event eCRF should be 
updated by changing the event from “non-serious” to “serious,” providing the date that the event 
became serious, and completing all data fields related to serious adverse events."  
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. 
 
Serious Adverse Event 
All events that meet the definition of a serious adverse event will also be reported by e-mail to 
andrea.visentin@unipd.it and sonia.faoro@aopd.veneto.it within 24 hours of them becoming aware, 
using a CIOMS Report Form or a Pregnancy Questionnaire form. This timeframe also applies to 
additional new information (follow-up) on previously reported SAEs. 
All serious AEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the following 
occurs: 
● 
the event resolves 
● 
the event stabilizes 
● 
the event returns to baseline, if a baseline value/status is available 
● 
the event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct 
● 
it becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of due 
diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 

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AE. The cause of death of a subject in a study, whether or not the event is expected or associated 
with the product under study, is considered a serious adverse event. 
The investigator will decide if these events are related to the protocol treatment (i.e. not related, 
doubtful, possible, probable, very likely) and the decision will be recorded on the form, if 
necessary with the reasoning of the investigator. 
 
Pregnancies 
Pregnancies occurring while subjects are on study drug or within 26 weeks after a subject’s last dose 
of study drug or pregnancy of the partner are considered events to be reported immediately to 
Sponsor. If the subject is on study drug, the study drug is to be discontinued immediately and the 
subject is to be instructed to return any unused portion of the study drug to the Investigator. The 
pregnancy must be reported to Sponsor using a Pregnancy Questionnaire Form. 
The Investigator will follow the subject until completion of the pregnancy, and must notify the 
Sponsor of the outcome within 5 days or as specified below. The Investigator will provide this 
information as a follow-up to the initial pregnancy report. If the outcome of the pregnancy meets the 
criteria for immediate classification as a SAE (i.e., spontaneous abortion [any congenital anomaly 
detected in an aborted foetus is to be documented], stillbirth, neonatal death, or congenital anomaly), 
the Investigator should follow the procedures for reporting SAE. All neonatal deaths that occur 
within 30 days of birth should be reported, without regard to causality, as SAE. In addition, any infant 
death after 30 days that the Investigator suspects is related to the in utero exposure to the study drug 
should also be reported. In the case of a live “normal” birth, the Sponsor should be advised as soon 
as the information is available. Any suspected fetal exposure must be reported to Sponsor within 24 
hours of being made aware of the event. The patient should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counselling. 
 
Adverse Event of Special Interest (AESI) 
Specific AEs or groups of AEs will be followed as part of standard safety monitoring activities. These 
events will be reported to the Sponsor within 24 hours of awareness irrespective of seriousness (ie, 
serious and non-serious AEs) following the procedure described above for serious AEs and will 
require enhanced data collection. 
Within this trial these adverse events of any grade will be considered AESI: hypertension, atrial 
fibrillation, atrial arrhythmia, ventricular arrhythmia, bleeding, any cardiovascular event, sudden 
death, infections. 
 
Other Malignancies 
In addition to all routine AE reporting, all new malignant tumors, including solid tumors, skin 
malignancies, are to be reported for the duration of study treatment and during any protocol-
specified follow-up periods including post-progression follow-up for OS.  
 
All forms must be as complete as possible and written in English, including details of the current 
illness and serious adverse event and an assessment of the causal relationship between the event 
and the investigational product. The information not available at the time of the initial report must 
be documented on a follow-up form. 
The Investigator, in case of death, has to communicate the event also to his local Ethics Committee. 
Information about SUSAR will be forwarded by the Sponsor directly into the Eudravigilance 
database. Any question concerning SAE reporting can be directed to sponsor: 
Dr. Andrea Visentin 
e-mail address: andrea.visentin@aopd.veneto.it  
Phone: 0039 049 821 2298 
 
Addition Pharmacovigilance procedures 
The Investigator Sponsor is responsible for all pharmacovigilance activities in the Study, including, 
but not limited to, submitting all safety reports arising out of the Study to the applicable regulatory 

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authorities and the appropriate ethics committee(s), as required by the Study protocol, any 
applicable Institutional policy, or applicable laws and/or regulations, within the requisite, applicable 
timeframes. In addition, Investigator Sponsor shall send all SAEs (including both initial and follow-
up) following the treatment of Study Drug to BeiGene within agreed timeline. Safety reports of 
pregnancy exposures and special situations, as defined in the Protocol, shall be reported to BeiGene 
in the same manner as for SAEs. 
Reporting SUSARs  
 
SAE reported to the sponsor that is evaluated by the Investigator as related to the IMP and 
unexpected will be reported to the regulatory authorities (EMA Eudravigilance) and the ethics 
committee by the Promotor (QPPV) within the reporting timelines:  
- 
Fatal or life threatening SUSARs: not later than 7 days after the sponsor has information that the 
case fulfills the criteria for a fatal or life threatening SUSAR, and any follow up information within 
a further 8 days.  
- 
All other SUSARs: not later than 15 days after the sponsor for pharmacovigilance has information 
that the case fulfils the criteria for a SUSAR.  
SUSARs will be reported to the Qualified Person for Pharmacovigilance (QPPV) of Azienda Ospedale 
– Università di Padova with 24 hours according to the relevant Pharmacovigilant SOP of promoter. 
The QPPV is Dr Sonia Faoro, of the Pharmacy Unit.  
The 
CIOMS 
report 
form 
must 
be 
sent 
to 
sonia.faoro@aopd.veneto.it 
and 
andrea.visentin@aopd.veneto.it 
Phone: 049 821 1888. 
 
Study drugs quality complaint handling 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have an 
impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, and 
the sponsor, and are mandated by regulatory agencies worldwide. Any suspected any quality defect 
in zanubrutinib or its packaging, labelling will be reported to the Sponsor within 24 hours. 
 
19. Quality assurance Control of data consistency 
Computerized and manual consistency checks will be performed on newly entered forms; queries 
will be issued in case of inconsistencies. Consistent forms will be validated by the Data Manager to 
be entered on the master database. Inconsistent forms will be kept "pending" until resolution of the 
inconsistencies. 
 
On-site quality control 
In order to ensure that the study is conducted according to Good Clinical Practice (GCP), the sponsor 
will send to every single center an Investigator’s File, will organize Training Meetings in which 
principal investigators as well as collaborative investigators will be involved. In these meetings the 
following issues will be addressed: 
1. Regulatory procedures. 
2. Compulsory documents to be sent to the sponsor in order to be authorized to enroll patients. 
3. Study documents archive system. 
4. Patient information sheet and informed consent: how to approach the patient and where to 
archive the document. 
5. Biological samples centralization system. 
6. Patient selection criteria and registration procedure. 
7. CRFs, queries management. 
8. SAEs/SUSARs 
9. Main source documents to be sent to the sponsor 

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During the first Training Meeting, different operative procedures will be distributed and explained, 
procedures concerning patient selection criteria and registration procedures, CRFs and 
SAEs/SUSARs. All these will be in the Investigator’s File as well. During general meetings, a report 
concerning the conduction of the study will be distributed. In this report, up to date data can be found 
concerning not only accrual but also SAEs/SUSARs, list of participating centers and particular 
situations that may have arisen during the conduction of the trial. This report constitutes an 
important working tool for the Investigator and is also an up to date report to be periodically 
presented to the Ethics Committee. Furthermore, the statistical design and the precise accrual will 
be a method to select data that need to be verified. 
Central review procedures 
All samples are sent to a single laboratory (within 24 hours). Samples are then processed and 
distributed to different laboratories in order that the various analyses are carried out uniformly and 
using internationally recognized standards. This type of organizations allows a highly defined 
standard of diagnosis, as well as a uniform diagnostic work-up for all enrolled cases, and a closely 
monitored census of the illness during the course of the study. Besides, this system provides the same 
standard for all patients, otherwise not possible. 
 
20 Ethical considerations and Patient protection, Regulatory and legal obligations 
The responsible investigator will ensure that this study is conducted in agreement with either the 
Declaration of Helsinki (Tokyo, Venice, Hong Kong, Somerset West and Edinburgh amendments) 
(APPENDIX F) or the laws and regulations of the country, whichever provides the greatest protection 
to the patient. The protocol has been written, and the study will be conducted according to the ICH 
Harmonized Tripartite Guideline for Good Clinical Practice. The protocol will be approved by the 
Local, Regional or National Ethics Committees.  
 
Subject identification 
The name of the patient will not be asked for nor recorded at the sponsor. A sequential identification 
number will be automatically attributed to each patient registered in the trial. This number will 
identify the patient and must be included on all case report forms. 
A subject identification list should be archived in each site in the Investigator Site File. 
 
Informed consent 
All patients will be informed of the aims of the study, the possible adverse events, the procedures 
and possible hazards to which he/she will be exposed, and the mechanism of treatment allocation. 
They will be informed as to the strict confidentiality of their patient data, but that their medical 
records may be reviewed for trial purposes by authorized individuals other than their treating 
physician. An example of a patient informed consent statement is given as an appendix G to this 
protocol. It is the responsibility of the individual investigator to translate the enclosed informed 
consent document. The translated version should be dated and version controlled. The translated 
informed consent form is part of the documents to be submitted to the ethics committee for approval. 
The competent ethics committee for each institution must validate local informed consent 
documents before the center can join the study. It is the responsibility of the Local Ethical Committee 
to guarantee that the translation is conforming to the ICH-GCP guidelines. It will be emphasized that 
the participation is voluntary and that the patient is allowed to refuse further participation in the 
protocol whenever he/she wants. This will not prejudice the patient’s subsequent care. Documented 
informed consent must be obtained for all patients included in the study before they are registered 
at the Sponsor. This must be done in accordance with the national and local regulatory requirements. 
For European Union member states, the informed consent procedure must conform to the ICH 
guidelines on Good Clinical Practice. 
 
21 Administrative responsibilities The Study Principal Investigators 
The principal investigator (in cooperation with the Data Center) will be responsible for writing the 

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protocol, reviewing all case report forms and documenting their review on evaluation forms, 
discussing the contents of the reports with the Data Manager and the Statistician, and for publishing 
the study results. They will also generally be responsible for answering all clinical questions 
concerning eligibility, treatment, and the evaluation of the patients. 
 
Study Principal Investigators: 
Dr. Andrea Visentin 
Azienda Ospedale Università Padova 
UOC Ematologia 
 andrea.visentin@aopd.veneto.it 
 
Prof. Livio Trentin 
Azienda Ospedale Università Padova  
UOC Ematologia livio.trentin@aopd.veneto.it 
 
Principal Investigators for neurological assessment: 
Prof. Chiara Briani 
Azienda Ospedale Università 
Padova Neurology clinic 
chiara.briani@unipd.it 
 
Dr. Bruno Ferrero 
AOU Città della Salute e della Scienza di Torino 
ferrerobruno_neuro@yahoo.it 
 
Principal Investigator for translation studies 
Dr. Simone Ferrero 
AOU Città della Salute e della Scienza di Torino 
simone.ferrero@unito.it 
 
22. Trial sponsorship and financing 
The promoter of the study is Azienda Ospedale - University Padova, which has also signed an 
agreement with BeOne medicine (formerly BeiGene) for the supply of study drugs free-of-charge and 
for a financial contribution to the study. 
 
23. Trial insurance 
The Sponsor has signed an insurance contract according to the “Decreto Ministeriale 14 luglio 2009 
- Requisiti minimi per le polizze assicurative a tutela dei soggetti partecipanti alle sperimentazioni 
cliniche dei medicinali”. 
 
24. Publication policy, study report and archiving of study documentation 
Once the trial has been closed and the Writing Committee has presented the main study publication, 
any participating center may, eventually, use its own data (data generated in its own center) for 
educational purposes, publications and presentations. These may be sent to Sponsor 30 days before 
the submision. The investigator is due to include sponsor’s name in any final publication. 
 
Authorship 
Authorship will be based on the ICMJE criteria. In details, the study coordinator and the sponsor will 
be responsible for substantial contributions to the conception or design of the work, the acquisition, 
analysis, interpretation of data for the work, drafting the work or revising it critically, agreement for 
all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of 
the work are appropriately investigated and resolved, approval of the final version of the manuscript. 
As a result, the final publication of the trial, results will be written by the study investigators on the 

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basis of the final analysis performed by the Sponsor. A draft of the manuscript will be submitted for 
review. Authors of the manuscript will be the investigators who have included at least 1 evaluable 
patient in the trial (by order of inclusion). Unless further agreement is made by investigators and the 
sponsor, all other participants or representatives of the sponsor who have contributed to the trial 
will be mentioned in the acknowledgment section of the manuscript. 
 
Responsibility for publication 
The manuscript will be sent to a major scientific journal after revision by the coordinator of the trial. 
The manuscripts will include an appropriate acknowledgment section, mentioning all investigators 
who have contributed to the trial, as well as supporting bodies. The Study Coordinator and Co- 
Coordinators must approve all publications, abstracts and presentations based on patients included 
in this study. This is applicable to any individual patient registered/randomized in the trial, or any 
subgroup of the trial patients. Such a publication cannot include any comparisons between 
randomized treatment arms nor an analysis of any of the study end-points unless the final results of 
the trial have already been published by the Study Coordinator. 
 
Study report 
An ICH-compliant integrated clinical and statistical report will be prepared upon completion of the 
study and data analysis.  
 
Archiving of study documentation 
Essential records, as listed below, must be retained by the investigator for as long as needed 
to comply with national and international regulations. The Sponsor will notify the 
investigators/institutions when the study-related records are no longer required. The 
investigator agrees to adhere to the document retention procedures by signing the protocol. 
 
Essential documents include for example: 
○ IRB/EC approvals for the study protocol and all amendments 
○ All source documents and laboratory records 
○ Patients' informed consent forms (with study number and title of trial) 
○ Any other pertinent study document. 
 
 
25. Investigator authorization procedure 
Investigators will be authorized to register and enroll patients in this trial only when they have 
returned to Azienda Ospedale - Università Padova: 
- The (updated) list of the normal ranges, in their own institution, of all laboratory data required by 
the protocol, preferably signed and dated by the head of the laboratory. 
- A signed conflict of interest disclosure form. 
- A copy of the favorable opinion of their local or national (whichever is applicable) ethics committee 
mentioning the documents that have been reviewed (incl. version number and date of documents) 
and indicating the list of the ethics committee members. 
- A copy of the translated, if applicable, and adapted, if changed by the Ethics Committee, (according 
to all national requirements), Informed Consent, clearly mentioning the version number and the 
date. 
- The coordinator of the pharmacist who will be responsible for the trial medication (for any trial 
where the drug will be provided) 
- List of co-investigators who are authorized to work for this study 
The center specific applicable list of required documents will be included in the protocol activation 
package, with proper instructions as required. 
 
26. Patient registration procedure 

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Patient registration will only be accepted from authorized investigators (see "Authorization 
procedure"). A patient can be registered after verification of eligibility criteria. A patient who has not 
been registered before the first treatment administration will not be accepted in the study at a later 
date. An exhaustive list of questions to be answered during the registration procedure is included in 
the registration check-list, which is part of the case report forms. This check-list should be completed 
by the responsible investigator before the patient is registered. 
 
27. Forms and procedures for collecting data 
Case report forms and schedule for completion 
Data will be collected using e-CRFs, in REDCap, managed by Azienda Ospedale - Università Padova. 
The system allows for audit trails, logging all user activity and all pages viewed by every user. Only 
the data requested by the protocol will be gathered. 
Data flow 
In all cases, it remains the responsibility of the investigator to check that e-CRFs are sent to the 
Azienda Ospedale - Università Padova as soon as possible and that they are completely and correctly 
filled out. Azienda Ospedale - Università Padova will perform extensive consistency checks and issue 
electronic Query Forms in case of inconsistent data. The investigator (or an authorized staff member) 
will electronically answer these queries and sign the query forms. The Azienda Ospedale - Università 
Padova will subsequently verify the modifications. If an investigator (or an authorized staff member) 
needs to modify a CRF after the e-form has been sent to the Azienda Ospedale - Università Padova, 
he/she should notify the Data Center in creating a query. 
 
 
28 Monitoring procedures during the study 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. The sponsor 
expects that during site visits the relevant investigational staff will be available, the source 
documentation will be available and a suitable environment will be provided for review of study-
related documents. 
In accordance with regulatory guidelines, audits may be carried out for this study. The investigator 
is required to facilitate an audit by means of a site visit. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Patient privacy 
must, however, be respected. Similar auditing procedures may also be conducted by agents of any 
regulatory body reviewing the results of this study. The investigator should immediately notify the 
sponsor if they have been contacted by a regulatory agency concerning an upcoming inspection. 

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APPENDIX A: REFERENCES 
1. Notermans NC, Wokke JH, Lokhorst HM, Franssen H, van der Graaf Y, Jennekens FG. 
Polyneuropathy associated with monoclonal gammopathy of undetermined significance. A 
prospective study of the prognostic value of clinical and laboratory abnormalities. Brain. 1994 
117:1385-93. 
2. Falzone YM, Campagnolo M, Bianco M et al. Functioning and quality of life in patients with 
neuropathy associated with anti-MAG antibodies. J Neurol. 2018 Oct 10. 
3. Monaco S, Bonetti B, Ferrari S et al. Complement-Mediated Demyelination in Patients with IgM 
Monoclonal Gammopathy and Polyneuropathy. N Engl J Med 1990; 322:649-652 
4. Dogliotti I, Jiménez C, Varettoni M et al. Diagnostics in Waldenström's macroglobulinemia: a 
consensus statement of the European Consortium for Waldenström's Macroglobulinemia. 
Leukemia. 2022 Nov 26. doi: 10.1038/s41375-022-01762-3. 
5. Hays AP, Latov N, Takatsu M, Sherman WH. Experimental demyelination of nerve induced by 
serum of patients with neuropathy and an anti-MAG IgM M-protein. Neurology. 1987 
Feb;37:242-56. 
6. Tatum AH. Experimental paraprotein neuropathy, demyelination by passive transfer of human 
IgM anti-myelin-associated glycoprotein. Ann Neurol. 1993 May;33:502-6. 
7. Nobile-Orazio, Meucci N, Baldini L, et al. Long-term prognosis of neuropathy associated with 
anti- MAG Ig M M-proteins and its relation with immune therapies. Brain 2000; 123:710-717. 
8. Benedetti L, Briani C, Grandis M, et al. Predictors of response to rituximab in patients with 
neuropathy and anti-myelin associated glycoprotein immunoglobulin M. J Peripher Nerv Syst. 
2007 Jun;12:102-7 
9. Campagnolo M, Zambello R, Nobile-Orazio E et al. IgM MGUS and Waldenstrom-associated anti- 
MAG neuropathies display similar response to rituximab therapy. J Neurol Neurosurg 
Psychiatry. 2017 Dec;88:1094-1097. 
10. Dalakas MC, Rakocevic G, Salajegheh M, et al. Placebo-controlled trial of rituximab in IgM anti- 
myelin-associated glycoprotein antibody demyelinating neuropathy. Annals of Neurology 2009; 
65:286-93; 
11. Leger JM, Viala K, Nicolas G, et al. Placebo-controlled trial of rituximab in IgM anti-myelin- 
associated glycoprotein neuropathy. Neurology 2013; 80:2217-25. 
12. Lunn MP, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated glycoprotein 
paraprotein-associated peripheral neuropathies. Cochrane Database Syst Rev. 2016 Oct 
4;10:CD002827. 
13. Parisi M, Dogliotti I, Clerico M, et al. Efficacy of rituximab in anti-myelin-associated glycoprotein 
demyelinating polyneuropathy: Clinical, hematological and neurophysiological correlations 
during 2 years of follow-up. Eur J Neurol. 2022 Dec;29(12):3611-3622. doi: 10.1111/ene.15553. 
14. Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton's tyrosine kinase in B cells and 
malignancies. Mol Cancer. 2018 Feb 19;17:57. 
15. Dimopoulos MA, Trotman J, Tedeschi A, et al. Ibrutinib for patients with rituximab-refractory 
Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, 
multicentre, phase 3 trial. Lancet Oncol. 2017;18:241-250 
16. Treon SP, Tripsas CK, Meid K et al. Ibrutinib in previously treated Waldenström's 
macroglobulinemia. N Engl J Med. 2015 Apr 9;372:1430-40. 
17. Allain JS, Thonier F, Pihan M, et al. IGHV segment utilization in immunoglobulin gene 
rearrangement differentiates patients with anti-myelin-associated glycoprotein neuropathy 
from others immunoglobulin M-gammopathies. Haematologica. 2018 May;103:e207-e210. 
18. Treon SP, Xu L, Hunter Z. MYD88 Mutations and Response to Ibrutinib in Waldenström's 
Macroglobulinemia. N Engl J Med. 2015 Aug 6;373:584-6. 
19. Varettoni M, Zibellini S, Merli M, et al. Molecular remission is an independent predictor of 
progression-free survival in patients with Waldenström macroglobulinemia treated with 
chemo- immunotherapy: Results from the FIL_BIOWM study. Hematol Oncol. 2022 Oct 11. doi: 
10.1002/hon.3082. 
20. Castellani F, Visentin A, Campagnolo M, et al. The Bruton tyrosine kinase inhibitor ibrutinib 

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improves anti-MAG antibody polyneuropathy. Neurol Neuroimmunol Neuroinflamm. 2020 Apr 
13;7(4):e720. 
21. Tam CS, Opat S, D'Sa S, Jurczak W et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib 
in symptomatic Waldenstrom macroglobulinemia: the ASPEN study. Blood. 2020 Oct 
29;136(18):2038-2050. 
22. Dimopoulos M, Sanz RG, Lee HP, et al. Zanubrutinib for the treatment of MYD88 wild-type 
Waldenstrom macroglobulinemia: a substudy of the phase 3 ASPEN trial. Blood Adv. 2020 Dec 
8;4(23):6009-6018. 
23. Opat S, Tedeschi A, Linton K, et al. The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton 
Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal 
Zone Lymphoma. Clin Cancer Res. 2021 Dec 1;27(23):6323-6332. 
24. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory 
Chronic Lymphocytic Leukemia. N Engl J Med. 2022 Dec 13. doi: 10.1056/NEJMoa2211582. 
25. Drandi D, Genuardi E, Dogliotti I. Highly sensitive MYD88L265P mutation detection by droplet 
digital polymerase chain reaction in Waldenström macroglobulinemia. Haematologica. 2018 
Jun;103(6):1029-1037.

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APPENDIX B: NEUROLOGICAL SCALES 
 
Overall Neuropathy Limitations Scale (ONLS) 
 
Instruction: the examiner should question and observe the patient in order to determine the 
answers to the following questions. Note should be made of any other disorder other than 
peripheral neuropathy which limits function at the foot of the page. 
 
ARM SCALE 
 
Does the patient have any symptoms in their hands or arms e.g. tingling, 
numbness 
or weakness? (if “no”, please go to “legs” section) 
Yes 
No 
 
Is the patient affected in their ability to 
Not affected 
Affected but not 
Prevented 
Prevented 
Wash and brush their hair 
Turn a key in a lock 
Use a knife and fork together (or spoon, if knife 
and fork not used) 
Do or undo buttons or zips 
Dress the upper part of their body 
excluding buttons or zips 
 
If all these functions are prevented can the 
patients make purposeful movements with 
their hands or arms? 
Yes 
No 
Not applicable 
Arm Grade 
0 = Normal 
1= Minor symptoms in one or both arms but not affecting any of the functions listed 
2= Disability in one or both arms affecting but not preventing any of the functions 
listed 3= Disability in one or both arms preventing at least one but not all functions 
listed 
4= Disability in both arms preventing all functions listed but purposeful movement still 
possible 5= Disability in both arms preventing all purposeful movements 
SCORE=_____

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LEG SCALE 
Yes 
No 
Not applicable 
Does the patient have difficulty running 
or climbing stairs? 
Does the patient have difficulty with walking? 
Does their gait look abnormal? 
How do they mobilise for about 10 metres (i.e. 33 
feet)? 
Without aid 
With one stick or crutch or 
holding to someone’s arm 
With two sticks or crutches or one 
stick or crutch holding onto 
someone’s arm or frame 
With a wheelchair 
If they use a wheelchair, can they stand and walk 
1 metre with the help of one person? 
If they cannot walk as above are they able to 
make some purposeful movements of their legs 
e.g. reposition legs in bed? 
Does the patient use ankle-foot orthoses/braces 
?(please circle) 
If yes: (please circle) 
Right / 
left 
Leg Grade 
0= Walking/climbing stairs/running not affected 
1= Walking/climbing stairs/running is affected, but gait does not look 
abnormal 2= Walks independently but gait looks abnormal 
3= Requires unilateral support to walk 10 metres (stick, single crutch, one arm) 
4= Requires bilateral support to walk 10 metres (sticks, crutches, crutch and arm, frame) 
5= Requires wheelchair to travel 10 metres but able to stand and walk 1 metre with the help of one 
person 6= Restricted to wheelchair, unable to stand and walk 1 metre with the help of one person, but 
able to make some purposeful leg movements 
7= Restricted to wheelchair or bed most of the day, unable to make any purposeful movements of the legs 
SCORE: _________ 
Overall Neuropathy Limitation Scale = arm scale (range 0-5) + leg scale (range 0-
7); [range: 0 (no disability) to 12 (maximum disability)] 
 
TOTAL SCORE=_____ 
 
Is there any disorder, other than peripheral neuropathy, 
which affects the above functions 
Yes 
No 
If yes please describe: 

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Inflammatory Neuropathy Cause and Treatment (INCAT) Disability 
Scale Arm disability 
O = No upper limb problems 
1 = Symptoms, in one or both arms, not affecting the ability to perform any of the following 
functions: doing all zips and buttons; washing or brushing hair; using a knife and fork together; 
handling small coins 
2 = Symptoms, in one arm or both arms, affecting but not preventing any of 
the above mentioned functions 
3 = Symptoms, in one arm or both arms, preventing one or two of the above 
mentioned functions 
4 = Symptoms, in one arm or both arms, preventing three or all of the 
functions listed, but some purposeful movements still possible 
 
Leg disability 
O = Walking not affected 
1 = Walking affected, but walks independently outdoors 
2 = Usually uses unilateral support (stick, single crutch, one arm) to walk 
outdoors 
3 = Usually uses bilateral support (sticks, crutches, frame, two arms) to walk 
outdoors 
4 = Usually uses wheelchair to travel outdoors, but able to stand and walk a 
few steps 
5 = Restricted to wheelchair, unable to stand and walk a few steps with help 
 
Overall disability = Sum of arm and leg disability

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INCAT Sensory Sum Score (ISS). 
 
The ISS ranges from 0 (normal sensation) to 20 (most severe sensory deficit) and is composed of the 
summation of the following sensation qualities: 
■ 
Pinprick arm grade (range 0-4) 
■ 
Vibration arm grade (range 0-4) 
■ 
Pinprick leg grade (range 0-4) 
■ 
Vibration leg grade (range 0-4) 
■ 
Two-point discrimination grade (range 0-4) 
Pinprick is tested with the sharp end of an esthesiometer, subjects indicate normal or abnormal. 
Paresthesia, dysesthesia or hyperesthesia are to be scored as abnormal. Normal reference point: face. 
Vibration sense is tested using the graduated Rydel-Seiffer tuning fork, measures obtained are compared 
with the reported normative threshold values. 
Pinprick and vibration sense examination take place distal to proximal and only the highest extension of 
dysfunction of the most affected arm and leg are recorded separately for both qualities. 
 
 
 
A,B: index fìnger (dorsum distal interphalangeal joint); C: ulnar styloid process; D: medial humerus 
epicondyle; E: acromioclavicular joint; F,G: hallux (dorsum inter-phalangeal joint); H: medial malleolus; I: 
patella; J: anterior superior iliac spine; K: index finger (ventral side: distal phalanx) 
 
 
 
 
 
 

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Inflammatory Rasch-built Overall Disability Scale (I-RODS) 
 
I- RODS is a 24-item scale, with each item representing a common, daily activity. 
 
The items range in difficulty from very easy (“reading a newspaper/book” and “eating”) to very difficult 
(“standing for hours” and “running”) 
 
The patient assigns a score between 0 and 2 to each item as follows: 
0 = impossible to perform 
1 = performed with difficulty 
2 = easily performed 
 
List of Daily Activities 
1. Reading 
2. Eating 
3. Brushing teeth 
4. Washing upper body 
5. Sitting on toilet 
6. Making sandwich 
7. Dressing upper body 
8. Washing lower body 
9. Moving chair 
10. Turning key in lock 
11. Going to general practitioner 
12. Taking shower 
13. Doing dishes 
14. Doing shopping 
15. Catching object (e.g., ball) 
16. Bending and picking up object 
17. Walking one flight of stairs 
18. Travelling by public transportation 
19. Walk while avoiding obstacles 
20. Walking up to 1 km outside 
21. Able to carry and put down heavy object (about 10 kg) 
22. Dancing 
23. Standing for hours 
24. Running

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Medical Research Council (MRC) muscle scale 
The muscle scale grades muscle power on a scale of 0 to 5 in relation to the maximum expected for that 
muscle. 
 
 
Numeric Rating Scale (NRS) 
 
The Numeric Rating Scale (NRS) is the simplest and most commonly used numeric scale in which the 
child rates the pain from 0 (no pain) to 10 (worst pain). 
 
 
 
 
 
9-hole peg test 
It is used to measure finger dexterity in patients with various neurological diagnoses 

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APPENDIX C: STUDY DRUGS TOXICITIES 
A listing of expected adverse drug reactions, defined as adverse events experienced by patients 
receiving zanubrutinib monotherapy that the sponsor considers expected for the purpose of 
determining requirements for expedited reporting, is presented in the Table below. This section 
outlines expected serious adverse reactions for regulatory purposes and the information within the 
RSI section does not represent a comprehensive overview of the zanubrutinib safety profile. Fatal 
and life- threatening events are considered unexpected. 
Expected Adverse Drug Reactions 
 

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Source: zanubrutinib IB, 14April 2023

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APPENDIX D: Interaction with other medicinal products and other forms of interaction 
Clinical drug-drug interaction study with zanubrutinib showed that co-administration of zanubrutinib 
with the strong CYP3A inducer rifampin decreased AUC0-∞ of zanubrutinib by 13.5-fold in healthy 
subjects. Co- administration of zanubrutinib with strong CYP3A inhibitor itraconazole increased AUC0-
∞ of zanubrutinib by 3.8-fold. These results are consistent with the role for CYP3A isoenzymes as the 
principal metabolic pathway for zanubrutinib. 
Administration of zanubrutinib with strong/moderate CYP3A inhibitors or CYP3A inducers and 
grapefruit juice and Seville oranges should be used with caution as they may affect the metabolism of 
zanubrutinib. 
If all possible, patients are encouraged not to use strong/moderate CYP3A inhibitors and inducers and 
should consider using alternative agents. If these agents will be used, follow the dose modification table 
in Table 3. The medical monitor should be consulted in these situations. Please refer to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list. 
 
Dose Modification Table for zanubrutinib when Co-Administered with Strong/Moderate CYP3A 
Inhibitors or Inducers 
 
CYP3A 
Co-administered Drug 
Recommended use 
Inhibition 
Strong CYP3A inhibitor (eg. ketoconazole, 
conivaptan, 
clarithromycin, 
indinavir, 
itraconazole, 
lopinavir, 
ritonavir, 
telaprevir, posaconazole, voriconazole) 
80 mg once daily 
Moderate 
CYP3A 
inhibitor 
(eg. 
erythromycin, ciprofloxacin, diltiazem, 
dronedarone, fluconazole, verapamil, 
aprepitant,   imatinib,   grapefruit 
products) 
80 mg twice daily 
Induction 
Strong 
CYP3A 
inducer 
(eg. 
carbamazepine, phenytoin, rifampin, St. 
John’s wort) 
Avoid 
concomitant 
use; 
Consider alternative agents 
with less induction potential. 
Moderate CYP3A inducer (eg. 
bosentan, efavirenz,
 
etravirine, 
modafinil, 
nafcillin) 
160 mg twice daily, use with 
caution; Monitor for potential 
lack of efficacy. 
 
CYP3A INHIBITORS AND INDUCERS 
Strong CYP3A Inhibitors 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
Protease inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
Moderate CYP3A Inhibitors 
Antibiotics: ciprofloxacin, erythromycin 
Antifungals: fluconazole, clotrimazole 
 

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Protease inhibitors: amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir 
Calcium channel blockers: diltiazem, verapamil 
Tyrosine kinase inhibitors (anticancer): imatinib, crizotinib 
Food products: grapefruit juice (citrus paradisi juice) 
Herbal medications: Schisandra sphenanthera 
Others: amiodarone, aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam 
Strong/Moderate CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), 
St. John’s wort (hypericum perforatum), enzalutamide, mitotane, bosentan, efavirenz, etravirine, 
modafinil 
Abbreviation: CYP: cytochrome P450. 
Note: The list of drugs in this table is not exhaustive. Please refer to the prescribing information of 
concomitant medication to check for CYP3A inhibition or induction risks or contact the medical 
monitor of the protocol. 
Source: Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, 
Drug Development and Drug Interactions and Inducers. Flockhart DA. Drug Interactions: Cytochrome 
P450 
Drug 
Interaction 
Table. 
Indiana 
University 
School 
of 
Medicine. 
http://medicine.iupui.edu/flockhart/table.htm 
 
 
SENSITIVE CYP2C8, CYP2C9, AND CYP2C19 SUBSTRATES OR CYP2C8, CYP2C9, AND 
CYP2C19 SUBSTRATES WITH A NARROW THERAPEUTIC INDEX 
CYP2C8 Substrates 
CYP2C9 Substrates 
CYPC19 Substrates 
repaglinide1 
celecoxib 
Anti-epileptics: 
paclitaxel 
phenytoin2 
S-mephenytoin1,2 
warfarin2 
Proton-Pump Inhibitors 
lansoprazole1 
omeprazole1 
Abbreviations: AUC, area under the plasma concentration time curve; CYP, cytochrome P450; NTI, 
narrow therapeutic index. 
1 Sensitive substrates: Drugs that exhibit an area under the plasma concentration time curve (AUC) 
ratio (AUCi/AUC) of 5-fold or more when coadministered with a known potent inhibitor. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious 
safety concerns (eg, Torsades de Pointes). 
Note: The list of drugs in this table is not exhaustive. Please refer to the prescribing information of 
concomitant medication to check for drug interaction information or contact the medical monitor of 
the protocol. 
Source: Food and Drug Administration Center for Drug Evaluation Research (CDER). FDA Guidance 
for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing and 
Labeling Recommendations. 2012.

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APPENDIX E: CENTRALIZATION OF SAMPLES TO PADOVA 
LABORATORY 
 
cfDNA samples will be collected at each of the participating sites and centralized to the unit of 
Padova and analyzed in the laboratory of Padova or of Torino. 
 
Padova address: 
Dr.ssa Federica Frezzato 
Campus biomedico Pietro d’Abano -  
laboratorio Ematologia 
Via G. Orus 2b 
35131 Padova – Italy 
Phone: +39-049-821 7729 
study coordinator +39-049-821 7809 
TURIN address: 
Prof. Simone Ferrero/Dr.ssa Daniela Drandi 
Laboratorio Biologia Molecolare 
c/o laboratorio Ematologia Universitaria 1 AOU 
Città della Salute e della Scienza di Torino, Via 
Genova 3, (Piano Terra) 
10126 Torino – Italy 
Phone: +39-011-633/6884/4251/4220 
 
 
Samples collection 
PB collected as per clinical practice are to be centralized to the assigned central laboratory 
according to the below reported scheme: 
Time-points 
Peripheral Blood 
Baseline (T0) 
10 ml x 2 in cell-free 
DNA BCT tubes 
Every 6 months 
till month +24 or 
till month 48 for 
responding 
patients 
10 ml x 2 in cell-free 
DNA BCT tubes 
month +24 
10 ml x 2 in cell-free 
DNA BCT tubes 
month +48 
10 ml x 2 in cell-free 
DNA BCT tubes 
All samples must be stored at room temperature and centralized as soon as possible to the central 
laboratory. 
 
Operative considerations for plasma and WBC cells collection 
 
PB samples for molecular analyses on cfDNA of diagnostic materials should be collected in 2 Cell-
Free DNA BCT tubes [Streck’s black/baige vacutainers]. 
 
1) 
20 ml of PB will be collected in 2 Cell-Free DNA BCT tubes (Streck’s, 10 ml each). 
 
Cell-Free DNA BCT is a direct draw whole blood collection tube intended for collection, stabilization 
and transportation of plasmatic circulating tumor DNA (ctDNA). The formaldehyde-free 
preservative reagent contained in Cell-Free DNA BCT stabilizes nucleated blood cells, preventing the 
release of cellular genomic DNA, and inhibits nuclease-mediated degradation of ctDNA, contributing 
to the overall stabilization of ctDNA. Samples collected in Cell-Free DNA BCT tubes are stable for up 
to 14 days at room temperatures, allowing convenient sample collection, transport and storage 
(Fig1).  
 

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Fig1. Cell-Free DNA BCT specification 
 
 
 
 
 
 
Since Cell-Free DNA BCT CE contains 
chemical additives, it is important to avoid 
possible backflow from the tube. To guard 
against backflow, observe the following 
precautions: 
2) 
keep patient’s arm in the downward 
position during the collection procedure; 
3) 
hold the tube with the stopper in the uppermost position so that the tube contents do not 
touch the stopper or the end of the needle during sample collection; 
4) 
release tourniquet once blood starts to flow in the tube, or within 2 minutes of application. 
Fill tube completely. 
5) 
remove tube from adapter and immediately mix by gentle inversion 8 to 10 times. Inadequate 
or delayed mixing may result in inaccurate test results. One inversion is a complete turn of 
the wrist, 180 degrees, and back (Fig 2). 
 
Fig2. Cell-Free DNA BCT tubes after PB recovering 
 
When stored at 18°C - 30°C, unused Cell-Free DNA BCT is stable through expiration 
date. Do not freeze unfilled Cell-Free DNA BCT. 
Do not refrigerate or freeze Blood collected in Cell-Free DNA BCT. 
 
Operative procedures for samples storage 
 
Plasma selection/collection from BCT or EDTA tubes. 
6) Centrifuge tubes at 1.300xg for 13 minutes at room temperature. 
7) Collect Plasma in separate 15 ml tube and centrifuge again at 1800xg for 10 minutes at room 
temperature. 
Cell-Free DNA BCT 
specification 
Blood Draw Volume 
10.0 ml 
Anticoagulant 
K3EDTA 
Additive 
Proprietary Stabilizing 
Agent 
Storage Prior to use 
Room Temperature 
Shipment temperature 
Room Temperature 

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8) Store plasma at -80°C in 1ml aliquots. 
 
 
B-CELLS collection from BM EDTA and PB leftover after plasma collection 
Resuspend the BM sample in erythrocytes lysis buffer (NH4Cl) (1:5 dilution) and the leftover blood 
(after plasma recovery) from BCT in erythrocytes lysis buffer (NH4Cl) (1:2 dilution). Leave 15 
minutes at room temperature (lying flat at dark) then centrifuge 15 minutes at 450xg at room 
temperature. Discard the supernatant, resuspend the pellet in 10-15 ml of NH4Cl and centrifuge 10 
minutes at 450xg at room temperature. Remove supernatant, resuspend in PBS or 0.9% NaCl (q.s.). 
Dispense 5-10x106 cells in each tube, centrifuge 1 minute at 13000xg and discard supernatant. Cells 
can now be stored indefinitely, as dried pellets, at -80°C for further DNA extraction 
 
ddPCR for MYD88 L265P 
 
Mutation detection assay is reported in Drandi D et al.25. A single set of primers is combined with 
two competitive probes in two assays, one for MYD88L265P labeled with FAM, and one for MYD88WT 
labeled with HEX. 
In the Pre-PCR zone, prepare the 20X primer and probe mix and the ddPCR reaction mix. One ddPCR 
master mix must be created for each assay to perform 3 replicates per sample. Each reaction must 
include at least 2 replicates of POSITIVE CONTROL; 3 replicates of each samples; 3 replicates of WT 
control sample; 3 replicates of no template control (NTC). Prepare the ddPCR mix for a volume 
increased by 10% (for one replicate: 22ul instead of 20ul) to be sure to have enough reaction mix 
volume for each replicate. Dispense the reaction mix in one well, based on the number of technical 
replicates needed. In the DNA zone, load the amount of gDNA (20ng/ul), for 3 replicates 49.5ul 
(16.5x3) of mix add 16.5lzl (5.5x3) of gDNA. Vortex, spin-down and then pipet the sample few times 
before add the gDNA to the mix. Seal carefully the plate or the strips with optical adhesive film or 
caps, mix and spin down briefly. From this well, 20ul of mix will be taken for, droplet generation, for 
each replicate. Proceed with droplets generation, loading 20ul of reaction mix and 60ul of droplet 
generation oil into the proper DG8 cartridge wells. Transfer the plate to a thermocycler and start the 
amplification using the following thermal protocol: 95 °C for 10 min; then 40 cycles of 94 °C for 30 s, 
55 °C for 1 min; 98 °C for 10 min. Load the post-PCR 96- wells plate into a QX200 droplet reader 
according to the manufacturer instruction. Perform the analysis by QuantaSoft Analysis Pro 1.0.596 
(Bio-Rad Inc.). For ddPCR analysis the following criteria should be met: a) only replicates with ≥ 9000 
droplets must be considered for the analysis; b) a threshold, determined for positive control and WT, 
should be used for the unknown samples and should be similar in different plates; c) positive control 
samples should show a reproducible ratio between experiments. Results can be expressed as 
MUT/WT (a/b) ratio. Cut-off ratio for positivity results is referred to the highest MYD88L265P level 
detected within the control group of healthy subject samples or MM patients (MYD88WT). Cut-off 
value should always be indicated. (i.e. MUT/WT ratio 3.4E-4 as cut off for negativity). 
 
 
APPENDIX F: World Medical Association Declaration of Helsinki 
Ethical Principles for Medical Research Involving Human Subjects 
 
World Medical Association 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 
1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 

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53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification 
added) 55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification 
added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on 
identifiable human material and data. The Declaration is intended to be read as a whole and each of 
its constituent paragraphs should be applied with consideration of all other relevant paragraphs. 
 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
The WMA encourages others who are involved in medical research involving human subjects to 
adopt these principles. 
 
General Principles 
 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration”, and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care”. 
 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfillment of this duty. 
 
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
 
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
 
7. Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the 
physician or other health care professionals and never with the research subjects, even though they 
have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
 

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12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
Risks, Burdens and Benefits 
 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. When the 
risks are found to outweigh the potential benefits or when there is conclusive proof of definitive 
outcomes, physicians must assess whether to continue, modify or immediately stop the study. 
 
Vulnerable Groups and Individuals 
 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood 
of being wronged or of incurring additional harm. All vulnerable groups and individuals should 
receive specifically considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable 
group. In addition, this group should stand to benefit from the knowledge, practices or interventions 
that result from the research. 
 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
 
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. The protocol should contain a statement of the ethical 
considerations involved and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, institutional 

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affiliations, potential conflicts of interest, incentives for subjects and information regarding 
provisions for treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. In clinical trials, the protocol must also describe appropriate 
arrangements for post-trial provisions. 
 
Research Ethics Committees 
 
23. The research protocol must be submitted for consideration, comment, guidance and approval to 
the concerned research ethics committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the researcher, the sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious AEs. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers must 
submit a final report to the committee containing a summary of the study’s findings and conclusions. 
 
Privacy and Confidentiality 
 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information. 
 
Informed Consent 
 
25. Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, 
no individual capable of giving informed consent may be enrolled in a research study unless he or 
she freely agrees. 
 
26. In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of 
the study and the discomfort it may entail, post-study provisions and any other relevant aspects of 
the study. The potential subject must be informed of the right to refuse to participate in the study or 
to withdraw consent to participate at any time without reprisal. Special attention should be given to 
the specific information needs of individual potential subjects as well as to the methods used to 
deliver the information. After ensuring that the potential subject has understood the information, 
the physician or another appropriately qualified individual must then seek the potential subject’s 
freely-given informed consent, preferably in writing. If the consent cannot be expressed in writing, 
the non-written consent must be formally documented and witnessed. All medical research subjects 
should be given the option of being informed about the general outcome and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
 
28. For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the group represented by the potential subject, the research cannot instead be 
performed with persons capable of providing informed consent, and the research entails only 

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minimal risk and minimal burden. 
 
29. When a potential research subject who is deemed incapable of giving informed consent is able to 
give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorized representative. The potential subject’s dissent 
should be respected. 
 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group. In such circumstances 
the physician must seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorized representative. 
 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from 
the study must never adversely affect the patient-physician relationship. 
 
32. For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
 
Use of Placebo 
 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those 
of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention andt he patients who receive any intervention less 
effective than the best proven one, placebo, or no intervention will not be subject to additional risks 
of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care 
must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process. 
 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human subjects and are accountable for the 

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completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorized representative, may use an unproven intervention 
if in the physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. This intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information must be recorded.