Clinical trial NCT05093530
Conditions: Viral Respiratory Tract Infection
Sponsor: Pneumagen Ltd.
Start date: 2021-10-12; Completion date: 2022-04-05
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1, single-centre, randomised, placebo-controlled first in human study in healthy subjects. The study will assess the safety and tolerability of single-ascending (Part A) and multiple-ascending (Part B) doses of Neumifil, administered intranasally.

Detailed description:
Part A will include up to 36 healthy subjects in up to 5 groups. 6 subjects will be enrolled in Groups A1-A3 and 9 subjects will be enrolled in Groups A4 and A5. All subjects will receive a single intranasal dose of Neumifil or placebo. In Groups A1-A3, 4 subjects will receive Neumifil and 2 will receive matching placebo. In Groups A4 and A5, 6 subjects will receive Neumifil and 3 will receive matching placebo. The planned dose levels are: 0.028 mg (Group A1), 0.085 mg (Group A2), 0.28 mg (Group A3), 0.885 mg (Group A4), and 2.8 mg (Group A5). Additional dose levels may be assessed in up to 2 optional groups of up to 9 subjects each (Groups A6 and A7).

Subjects will be screened within 35 days before their dose of trial medication and reside at the Investigator site from the day before their dose (Day -1) until approximately 24 hours after dosing (Day 2). They will return for a follow-up visit on Day 8-9.

Part B will include up to 24 healthy subjects in up to 3 groups of 8 subjects (Groups B1-B3). Subjects will receive once-daily intranasal doses of Neumifil or placebo for 7 days. In each group, 6 subjects will receive Neumifil and 2 subjects will receive matching placebo.

The starting dose level (dose and dose regimen) for Group B1 will be decided after review of safety and tolerability data from at least 3 dose levels in Part A, and will be no higher than a dose that has previously been shown to cause no safety concerns in Part A . An additional dose level may be explored in 1 optional group of up to 8 subjects (Group B4).

Subjects will be screened within 35 days before their dose of trial medication and reside. at the Investigator site from the day before their first dose (Day -1) until about 24 hours after their last dose (Day 8). Subjects will attend an outpatient visit on Days 15-16. They will return for a follow-up visit on Days 21-23.

During the study, dose levels for study groups will be determined by a Safety Review Committee in accordance with criteria defined in the study protocol and the Investigator site operating procedures. Dose levels will only be increased if the safety and tolerability of previous dose levels are considered to be acceptable by the Safety Review Committee.

Arms: arm 1: Neumifil will be administered intranasally using an Aptar delivery system. Each dose will consist of 0.5ml to each nostril, with adjusted concentrations of solution to enable dose ranging. Participants in Part A will receive a single dose of Neumifil and participants in Part B will receive once daily doses of Neumifil for 7 days according to the randomization.

Ascending single doses for Part A are anticipated to be 0.028mg (group A1), 0.085mg (group A2), 0.28mg (group A3), 0.885mg (group A4) and 2.8mg (group A5). Two further groups of up to 9 subjects may be investigated. The planned dose levels may change following review of the safety and tolerability of previous doses. The maximum dose will not exceed 2.8mg.

The starting dose level (dose and dose regimen) in Part B will be determined following review of the safety and tolerability of at least 3 dose levels in part A and subsequent dose levels will be determined following review of the safety and tolerability of previous doses. arm 2: Placebo will be administered intranasally using an Aptar deliver system. Each dose will consist of 0.5ml to each nostril. Participants in Part A will receive a single dose of placebo according to the randomization and participants in Part B will receive once daily doses of placebo for 7 days according to the randomization schedule.
Interventions: intervention 1: Neumifil intervention 2: Placebo
Intervention descriptions: intervention 1: Neumifil contains the active ingredient HEX17, a multivalent, glycan-targeting carbohydrate binding module (CBM). HEX17 CBM is suspended in an aqueous buffer solution containing 20 mM sodium phosphate, 50 mM NaCl (at pH 6.3), 5 % (v/v) glycerol and 0.5 % (v/v) polysorbate 80. intervention 2: Aqueous buffer solution containing 20 mM sodium phosphate, 50 mM NaCl (at pH 6.3), 5 % (v/v) glycerol and 0.5 % (v/v) polysorbate 80.

Protocol documents:
Prot_SAP_000.pdf: 
Safety and tolerability of single and repeated Neumifil 
Trial Codes:  20-021 and PNG-NMF-101 
 
 
Protocol Version 3, dated 15 December 2021   
Page 1 of 72 
 
 
Pneumagen Ltd 
Trial Protocol 
Confidential 
 
Trial title 
A two-part, randomised, double-blind, 
placebo-controlled, ascending dose study to assess the 
safety and tolerability of single and multiple doses of 
Neumifil (a novel drug candidate with potential for 
treatment of COVID-19). 
Short title 
Safety and tolerability of single and repeated doses of 
Neumifil 
Version and date of protocol 
Version 3, dated 15 December 2021    
HMR code  
20-021 
Sponsor code  
PNG-NMF-101 
EudraCT no 
2021-001946-36 
Trial medication 
Neumifil 
Phase of trial 
Phase 1 
Place of trial 
HMR 
Cumberland Avenue 
London NW10 7EW 
Tel:  020 8961 4130 
 
Fax:  020 8961 8665 
Principal investigator 
 
HMR 
Sponsor 
Pneumagen Ltd 
Kinburn Castle, Doubledykes Road 
St. Andrews, Fife 
Scotland KY16 9DR 
Tel:  
  
Email:  
 
Planned dates of trial 
October 2021 to February 2022 


Safety and tolerability of single and repeated Neumifil 
Trial Codes:  20-021 and PNG-NMF-101 
 
 
Protocol Version 3, dated 15 December 2021   
Page 2 of 72 
1 
Signatures 
The investigator and the sponsor have discussed this protocol.  The investigator 
agrees to perform the investigation and to abide by this protocol and any future 
agreed amendments, except in case of medical emergency. 
Principal investigator 
 
 
 
HMR 
Statistician 
 
HMR 
Sponsor 
 
Pneumagen CMO (consultant) 
 
 


Safety and tolerability of single and repeated Neumifil 
Trial Codes:  20-021 and PNG-NMF-101 
 
 
Protocol Version 3, dated 15 December 2021   
Page 3 of 72 
2 
Summary 
2.1 
Trial medication 
Neumifil is a first-in-class, multivalent, glycan-targeting carbohydrate binding 
module (CBM).  It is being developed as a nasal formulation to treat viral respiratory 
tract infections (RTIs), including those caused by SARS-CoV-2. 
2.2 
Objectives 
2.2.1 
Primary objectives 
Part A 
• To assess the safety and tolerability of single-ascending intranasal doses of 
Neumifil in healthy subjects. 
Part B 
• To assess the safety and tolerability of multiple-ascending intranasal doses of 
Neumifil in healthy subjects. 
2.2.2 
Exploratory objective 
• To determine the number of subjects contracting SARS-CoV-2 during the 7 days 
after receiving their (last) dose. 
• To assess the formation of Neumifil anti-drug antibodies (ADAs) after multiple-
ascending intranasal doses in healthy subjects (Part B only). 
• 
To assess plasma concentration of single- or multiple-ascending intranasal doses 
of Neumifil in healthy subjects to determine if intranasal administration results in 
systemic exposure. 
• 
To assess the concentrations of cytokines and chemokines in nasal secretions 
before dosing and after multiple intranasal doses of Neumifil (Part B only). 
2.3 
Endpoints 
2.3.1 
Primary endpoints 
Safety and tolerability:   
Clinically significant changes in:  vital signs (heart rate, blood pressure, respiratory 
rate, pulse oximetry, and temperature), 12-lead electrocardiogram (ECG), forced 
expiratory volume (FEV1), forced vital capacity (FVC), physical examination, nasal 
examination, laboratory safety tests (haematology, biochemistry and urinalysis), 
tolerability questionnaire, number and severity of adverse events (AEs) and serious 
AEs.  Safety endpoints will be assessed up to 7 days after dosing in Part A or up to 
14 days after the last dose in Part B. 


Safety and tolerability of single and repeated Neumifil 
Trial Codes:  20-021 and PNG-NMF-101 
 
 
Protocol Version 3, dated 15 December 2021   
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2.3.2 
Exploratory endpoint 
PD:  SARS-CoV-2 infection test, done at screening, before the first dose, on Day 8 
(Part B only), and at follow-up.  
Immunogenicity:  ADAs of Neumifil, as assessed by immunoglobulin A and G (IgA 
and IgG) concentration, derived from blood samples taken before the first dose and 
at follow-up (Part B only). 
Plasma concentrations of Neumifil:  Plasma concentrations of Neumifil after single 
doses on Day 1 in Part A, and after dosing on Days 1 and 7 in Part B. 
Cytokine and chemokine concentrations in nasal secretions:  Presence and 
concentration of cytokines and chemokines, measured by multiplex assay, in nasal 
wick samples collected on Day –1, Day 8, and at follow up (Part B only).  
2.4 
Type of trial 
This is a Phase 1, single-centre, randomised, placebo-controlled first-time-in-human 
(FTIH) study in healthy subjects.  The study is in 2 parts and will investigate 
single-ascending (Part A) and multiple-ascending (Part B) doses of Neumifil, 
administered intranasally.  
2.5 
Trial design and methods 
2.5.1 
Part A 
Part A is a randomised, double-blind, placebo-controlled, single ascending dose 
study.  Enrolment of up to 36 healthy subjects is planned, in up to 5 groups 
(Groups A1−A5).  Groups A1–A3 will consist of 6 subjects each and Groups A4 and 
A5 will consist of 9 subjects each.   
Subjects will receive a single intranasal dose of Neumifil or placebo.  In 
Groups A1−A3, 4 subjects will receive Neumifil and 2 will receive matching 
placebo.  In Groups A4 and A5, 6 subjects will receive Neumifil and 3 will receive 
matching placebo.   
The planned dose levels are:  0.028 mg (Group A1), 0.085 mg (Group A2), 0.28 mg 
(Group A3), 0.885 mg (Group A4), and 2.8 mg (Group A5).  Because Neumifil has 
never been given to humans before, each new ascending dose will be staggered via 
the use of sentinel subjects.  It is intended that subsequent groups will receive higher 
doses.  The dose will be escalated only if the safety and tolerability of the previous 
highest dose are acceptable, as determined by the Safety Review Group (SRG).  
Additional dose levels may be explored in up to 2 optional groups of 9 subjects 
(Groups A6 and A7). 
Subjects will be screened within 35 days before their dose of trial medication.  
Subjects will be resident on ward from 1 day before their dose (Day –1) until about 


Safety and tolerability of single and repeated Neumifil 
Trial Codes:  20-021 and PNG-NMF-101 
 
 
Protocol Version 3, dated 15 December 2021   
Page 5 of 72 
24 h after dosing (Day 2).  They will return for a follow-up visit 7–8 days after their 
dose (Day 8–9). 
2.5.2 
Part B 
Part B is a randomised, double-blind, placebo-controlled, multiple ascending dose 
study.   
Enrolment of up to 24 healthy subjects is planned, in up to 3 groups (Groups B1−B3) 
of 8 subjects each.  Subjects will receive once-daily intranasal doses of Neumifil or 
placebo for 7 days.  In each group, 6 subjects will receive Neumifil and 2 will 
receive matching placebo.     
Part B can start before completion of Part A.  The starting dose level (dose and dose 
regimen) for Group B1 will be decided after review of safety and tolerability data 
from at least 3 dose levels in Part A and will be no higher than a dose level that has 
previously been shown to cause no safety concerns in Part A (see section 8.5.3).  
Subsequent dose levels will be determined as described for Part A.  An additional 
dose level may be explored in 1 optional group (Group B4). 
Subjects will be screened within 35 days before their dose of trial medication.  
Subjects will be resident on ward from 1 day before their dose (Day –1) until about 
24 h after their last dose (Day 8).  Subjects will attend an outpatient visit at 7−8 days 
after their last dose (Days 15–16).  They will then return for a follow-up visit at 
13−15 days after their last dose (Days 21–23). 
2.6 
Trial population 
a 
Total Up to 60 healthy volunteers (up to 36 in Part A and up to 24 in Part B), 
excluding replacements 
b 
Age 
18–60 years 
c 
Inclusion criteria 
Normotensive male or female volunteers, deemed healthy on the basis of a clinical 
history, physical examination, ECG, vital signs, and laboratory tests of blood and 
urine; body mass index (BMI; Quetelet index) in the range 18.0–30.9 kg/m2; non-
smoker; FEV1 and FVC ≥ 80%; agree to follow the contraception requirements of the 
trial (section 11); agree not to donate blood or blood products during the study and 
for 3 months after dosing; able to give fully informed written consent. 
d 
Exclusion criteria 
Positive tests for hepatitis B & C, human immunodeficiency virus (HIV); severe 
adverse reaction to any drug; sensitivity to trial medication; known allergy to 
tetracycline antibiotics; drug or alcohol abuse, or regular intake of > 14 units of 
alcohol weekly; evidence of smoking in the last 3 months; use of over-the-counter 


Safety and tolerability of single and repeated Neumifil 
Trial Codes:  20-021 and PNG-NMF-101 
 
 
Protocol Version 3, dated 15 December 2021   
Page 6 of 72 
medication (with the exception of paracetamol, or vitamin or nutritional 
supplements) during the 7 days, or prescribed medication (with the exception of 
hormone replacement therapy [HRT]), including oral contraceptives, during the 
28 days, before the first dose of trial medication; receipt of a COVID-19 vaccine 
during the 7 days before the first dose of trial medication, or anticipate receiving a 
COVID-19 vaccine within the 7 days after a (final) dose of trial medication; 
participation in other clinical trials of unlicensed medicines, or loss of more than 
400 mL blood, within the previous 3 months; vital signs and ECG measurements 
outside the acceptable range; clinically relevant abnormal findings at the screening 
assessment; acute or chronic illness; clinically relevant abnormal medical history 
(including psychiatric disease or cancer) or concurrent medical condition (including 
respiratory disease or illness); immune suppressed status, resulting from disease or 
medication; possibility that volunteer will not cooperate; females who are pregnant 
or lactating, or who are sexually active and not using a reliable method of 
contraception (section 11); objection by general practitioner (GP) to trial 
participation. 
2.7 
Assessments 
The following assessments will be made. 
2.7.1 
Safety and tolerability   
Laboratory assessments (haematology, biochemistry and urinalysis), physical 
examinations, 12-lead ECGs, vital signs (heart rate, blood pressure, respiratory rate, 
pulse oximetry and temperature), nasal examinations, FEV1 and FVC will be done 
before and during dosing and frequently until the subject’s last visit in each study 
part.  Subjects will complete a tolerability questionnaire after each dose of Neumifil. 
AEs will be recorded from screening until the subject’s last visit in each study part.   
2.7.2 
Pharmacokinetics 
Blood samples for assay of Neumifil will be taken before and up to 3 h after dosing 
on Day 1 (Part A) and Days 1 and 7 (Part B). 
2.7.3 
Immunogenicity 
Blood samples for assay of Neumifil ADAs will be taken before dosing on Day 1, 
and on Day 22 (Part B only).  


Safety and tolerability of single and repeated Neumifil 
Trial Codes:  20-021 and PNG-NMF-101 
 
 
Protocol Version 3, dated 15 December 2021   
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2.7.4 
Pharmacodynamics 
Nasal wick samples for assay of cytokines and chemokines in nasal secretions 
 
 
 
 


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Protocol Version 3, dated 15 December 2021   
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3 
Contents 
 
1 
Signatures 
2 
2 
Summary 
3 
2.1 
Trial medication 
3 
2.2 
Objectives 
3 
2.2.1 
Primary objectives 
3 
2.2.2 
Exploratory objective 
3 
2.3 
Endpoints 
3 
2.3.1 
Primary endpoints 
3 
2.3.2 
Exploratory endpoint 
4 
2.4 
Type of trial 
4 
2.5 
Trial design and methods 
4 
2.5.1 
Part A 
4 
2.5.2 
Part B 
5 
2.6 
Trial population 
5 
2.7 
Assessments 
6 
2.7.1 
Safety and tolerability 
6 
2.7.2 
Pharmacokinetics 
6 
2.7.3 
Immunogenicity 
6 
3 
Contents 
8 
3.1 
Table of figures 
11 
3.2 
Table of tables 
11 
4 
List of abbreviations 
12 
5 
Trial personnel 
16 
6 
Introduction 
18 
6.1 
Background 
18 
6.1.1 
Viral respiratory tract infections 
18 
6.1.2 
COVID-19 
18 
6.1.3 
Treating respiratory tract infections 
19 
6.2 
Review of investigational medicinal product 
19 
6.2.1 
Neumifil 
19 
6.2.2 
In vitro and in vivo pharmacology 
20 
6.2.3 
Safety pharmacology 
21 
6.2.4 
Pharmacokinetics 
21 
6.2.5 
Toxicology 
22 
6.3 
Rationale for the trial 
23 
6.4 
Rationale for choice of dose(s) 
23 
6.4.1 
Starting dose 
23 
6.4.2 
Subsequent doses 
24 
6.5 
Assessment and management of risk 
25 
6.5.1 
Conducting the trial during the COVID-19 pandemic 
26 


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Protocol Version 3, dated 15 December 2021   
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7 
Objectives and endpoints 
27 
7.1 
Objectives 
27 
7.1.1 
Primary objectives 
27 
7.1.2 
Exploratory objective 
27 
7.2 
Endpoints 
28 
7.2.1 
Primary endpoints 
28 
7.2.2 
Exploratory endpoint 
28 
8 
Overall trial design 
28 
8.1 
Trial design 
28 
8.1.1 
Part A 
29 
8.1.2 
Part B 
30 
8.2 
Study flow chart 
31 
8.3 
Definition of the end of the trial 
32 
8.4 
Stopping criteria 
32 
8.4.1 
Trial stopping criteria 
32 
8.4.2 
Dose escalation stopping criteria 
32 
8.5 
Criteria for dose selection 
32 
8.5.1 
Review of data by the SRG 
32 
8.5.2 
Dose selection for Part A 
34 
8.5.3 
Dose selection for Part B 
34 
8.5.4 
Repeating a dose level or selection of a lower dose level (Parts A and B) 
34 
9 
Trial population 
35 
9.1 
Planned number of subjects 
35 
9.2 
Inclusion criteria 
35 
9.3 
Exclusion criteria 
35 
9.4 
Withdrawal of subjects from the trial 
37 
9.4.1 
Withdrawal of subjects 
37 
9.4.2 
Individual subject stopping criteria (Part B only) 
37 
9.4.3 
Replacement of withdrawn subjects 
38 
10 
Treatments 
38 
10.1 
Treatments administered 
38 
10.2 
Overdose 
39 
10.3 
Blinding 
39 
10.4 
Unblinding procedure 
39 
10.5 
Method of assigning subjects to treatment groups 
40 
10.6 
Selection and timing of dose for each subject 
41 
10.7 
Previous and concomitant treatment 
41 
10.8 
Assessment of compliance 
41 
11 
Dietary and lifestyle restrictions 
41 
12 
Procedures and observations 
43 
12.1 
Schedule of procedures 
45 


Safety and tolerability of single and repeated Neumifil 
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Protocol Version 3, dated 15 December 2021   
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12.1.1 Part A 
45 
12.1.2 Part B 
47 
12.2 
Sampling time points and additional tests 
49 
12.3 
Follow-up 
50 
12.4 
Methods 
50 
12.5 
Total volume of blood removed 
54 
13 
Trial materials 
55 
13.1 
Identity of test product 
55 
13.2 
Packaging and labelling 
56 
13.3 
Storage and accountability of IMP 
56 
14 
Adverse events 
56 
14.1 
Definitions of adverse events 
56 
14.2 
Procedures for recording adverse events 
57 
14.3 
Procedures for dealing with serious adverse events 
59 
14.4 
Procedures for handling withdrawals due to adverse events 
59 
14.5 
Procedures for reporting pregnancies 
60 
15 
Data management and quality assurance 
60 
16 
Statistical methods 
61 
16.1 
Statistical methods 
61 
16.1.1 Planned analyses 
61 
16.1.2 Statistical hypotheses 
61 
16.1.3 Analysis populations 
61 
16.1.4 General considerations for data analyses 
62 
16.1.5 Study population analyses 
62 
16.1.6 Safety data analyses 
62 
16.1.7 Plasma concentration data analyses 
64 
16.2 
Determination of sample size 
64 
17 
Ethical and regulatory requirements 
64 
18 
Trial documentation 
66 
18.1 
Protocol amendments 
66 
18.2 
Case report forms 
66 
18.3 
Reporting of results 
67 
19 
Obligations of the sponsor and investigator 
67 
19.1 
Monitoring, auditing and inspection 
67 
19.2 
Compensation of volunteers 
67 
19.3 
Confidentiality 
68 
19.4 
Publication 
68 
19.5 
Archiving 
68 
20 
Premature termination of the trial 
68 


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Protocol Version 3, dated 15 December 2021   
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21 
References 
69 
22 
Appendix 1:  Subject self-reported dosing and post-dosing experience 
71 
 
3.1 
Table of figures 
Figure 1:   
HEX17 hexavalent structure ............................................................................. 20 
Figure 2:  
Modifications made in the construction of HEX17 from parent CBM 
Sp2CBMTD ...................................................................................................... 20 
Figure 3 
Study flow chart ................................................................................................ 31 
 
3.2 
Table of tables 
Table 1 
Calculation of margins of safety for Neumifil, based on mg/kg bodyweight ... 24 
Table 2 
Calculation of margins of safety for Neumifil, normalised by nasal surface area 
 
 ........................................................................................................................... 24 
Table 3  
Planned doses in Part A .................................................................................... 29 
Table 4 
Subject and sentinel numbers ............................................................................ 40 
Table 5 
Acceptable deviation times (Part A) ................................................................. 49 
Table 6 
Acceptable deviation times (Part B) ................................................................. 49 
Table 7 
Laboratory safety tests ...................................................................................... 51 
Table 8 
Planned blood volume (Part A) ......................................................................... 55 
Table 9 
Planned blood volume (Part B) ......................................................................... 55 
 
 
 


Safety and tolerability of single and repeated Neumifil 
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Protocol Version 3, dated 15 December 2021   
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4 
List of abbreviations 
ABPI 
Association of the British Pharmaceutical Industry 
ACE2 
angiotensin-converting enzyme 2 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
AP 
alkaline phosphatase 
AR 
adverse reaction 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
 
AUCinf 
area under the concentration–time curve extrapolated to infinite 
time 
BMI 
Body Mass Index 
CBM 
carbohydrate binding module 
CI 
confidence interval 
cm 
centimetre(s) 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRP 
C-reactive protein 
CTA 
clinical trial authorisation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDTA 
ethylenediaminetetraacetic acid 
EU 
European Union 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
FSH 
follicle-stimulating hormone 
FTIH 
first time in human 
G 
G force 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
GMP 
Good Manufacturing Practice 
GLP 
Good Laboratory Practice 
GP 
General Practitioner 
h 
hour(s) 


Safety and tolerability of single and repeated Neumifil 
Trial Codes:  20-021 and PNG-NMF-101 
 
 
Protocol Version 3, dated 15 December 2021   
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Hb 
haemoglobin 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
HMR 
Hammersmith Medicines Research 
HRA 
Health Research Authority 
HRT 
hormone replacement therapy 
IB 
investigator's brochure 
ICH 
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IL-1 
interleukin-1 
IL-3 
interleukin-3 
IL-10 
interleukin-10 
IMP 
investigational medicinal product 
INR 
international normalised ratio 
IP-10 
interferon gamma-induced protein-10 
IUD 
intrauterine device 
IUS 
intrauterine system 
kD 
kilo Dalton 
kg 
kilogram(s) 
λz 
terminal rate constant 
LIMS 
laboratory information management system 
LRQ 
lower limit of reliable quantification 
MABEL 
minimum anticipated biological effect level 
MCH 
mean corpuscular haemoglobin 
MCHC 
mean corpuscular haemoglobin concentration 
MCP-1 
monocyte chemoattractant protein-1 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MIA(IMP) 
manufacturing authorisation for investigational medicinal 
products 
MIP-1α 
macrophage inflammatory protein-1α 
µg 
microgram(s) 
µl 
microlitre(s) 
min 
minute(s) 
mL 
millilitre(s) 


Safety and tolerability of single and repeated Neumifil 
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Protocol Version 3, dated 15 December 2021   
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mm 
millimetre(s) 
mm Hg 
millimetres of mercury 
MoS 
margin(s) of safety 
msec 
millisecond(s) 
NaCl 
sodium chloride 
ng 
nanogram(s) 
NOAEL 
no observed adverse effect level 
PCI 
potential clinical importance 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PK 
pharmacokinetic(s) 
PV 
pharmacovigilance 
QA 
quality assurance 
QC 
quality control 
QP 
qualified person 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected according to Fridericia’s formula 
RANTES 
regulated on activation, normal T cell expressed and secreted 
RBC 
red blood cells 
RBD 
receptor binding domain 
REC 
research ethics committee 
RES 
Research Ethics Service 
RMP 
risk mitigation policy 
RNA 
ribonucleic acid 
RSV 
respiratory syncytial virus 
RTI 
respiratory tract infection 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
serious adverse reaction 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SOP(s) 
standard operating procedure(s) 
SpO2 
peripheral arterial oxygen saturation 
SRG 
Safety Review Group 
SSAR 
suspected serious adverse reaction 
SUSAR 
suspected unexpected serious adverse reaction  
TD 
trimerisation domain   
TEAE 
treatment-emergent adverse event 
tmax 
time of maximum plasma concentration 
TNF-α 
tumour necrosis factor-α 


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Protocol Version 3, dated 15 December 2021   
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TOPS 
The Overvolunteering Prevention System 
UK 
United Kingdom 
ULN 
upper limit of normal 
WBC 
white blood cells 
 
 
 
 
 




Safety and tolerability of single and repeated Neumifil 
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Protocol Version 3, dated 15 December 2021   
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Demo IMP safety testing 
Wickham Laboratories Ltd 
Hoeford Point, Barwell Lane 
Gosport, Hampshire 
England PO13 0AU 
Tel:  +44 (0) 1329 226 695 
Email:  MicroAdmin@wickhamlabs.co.uk 
Assays of IMP concentration 
Alderley Analytical Ltd 
Alderley Park 
Macclesfield 
Cheshire 
SK10 4TG 
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6 
Introduction  
6.1 
Background 
6.1.1 
Viral respiratory tract infections 
Viral respiratory tract infections (RTI) are of enormous global concern, particularly 
with the emergence of the coronavirus disease 2019 (COVID-19) pandemic (caused 
by severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]).  Prophylactic 
approaches for viral RTIs, including coronaviruses such as SARS-CoV-2, influenza, 
and respiratory syncytial virus (RSV), are a significant unmet need.   
Vaccines are available for individual strains of influenza.  However, strain coverage 
is not universal, and hence the risk of low vaccine effectiveness continues year on 
year.  Furthermore, there is low efficacy of influenza vaccines in the ageing 
population1,2.  Additionally, while vaccines are being rolled out against 
SARS-CoV-2, efficacy in the immunocompromised and immunosenescent 
population is not yet fully understood, and there is a significant risk of vaccine 
escape via viral mutations.  Antivirals are also available to treat RTIs, but viral 
resistance remains a significant issue, and some antivirals (eg adamantanes) are no 
longer used for this reason.  Therefore, a pan-viral prophylactic agent will 
complement the current prevention strategies.  
6.1.2 
COVID-19 
The global pandemic of novel COVID-19 caused by SARS-CoV-2 began in Wuhan, 
China, in December 2019, and has since spread worldwide.  As of 09 August 2021, 
there have been more than 203 million reported cases and over 4 million deaths 
across nearly 200 countries, and the numbers are still growing.   
SARS-CoV-2 likely binds to epithelial cells in the nasal cavity.  From the initial 
infection, the virus propagates and migrates down the respiratory tract along the 
conducting airways.  For about 80% of the infected patients, the disease will be mild 
and mostly restricted to the upper and conducting airways; the most common 
symptoms at onset of illness are fever, new unproductive cough, fatigue, myalgia and 
loss of taste and smell.  Unfortunately, about 20% of infected patients will develop 
pulmonary infiltrates and typically develop dyspnoea.  Some of those patients will 
progress to a very severe disease phenotype which can result in hospitalisation, 
requirement for mechanical ventilation, and substantial morbidity and mortality. 
Several vaccines have now been approved for use, either by individual countries or 
groups of countries, such as the European Union (EU).  However, it is anticipated 
that it will take at least another 1–2 years until most of the world’s population can be 
vaccinated.  Also, vaccination may not achieve reliable protection for elderly or 
immune-compromised patients who also happen to be at highest risk for 
unfavourable clinical course of a SARS-CoV-2 infection.  Last but not least, virus 


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mutation may result in viral escape from vaccine-induced immunity.  It is therefore 
anticipated that there will be an ongoing need for efficacious therapeutic agents. 
6.1.3 
Treating respiratory tract infections 
Targeting of the host glycome is a well-established mechanism for infectious 
diseases, including viral RTIs, to infect cells, and as such provides an avenue of 
strong therapeutic potential. 
In the case of SARS-CoV-2, numerous studies3,4 support a major role for the virus-
surface Spike protein to facilitate cell entry by binding to host-cell angiotensin-
converting enzyme 2 (ACE2) receptors.  
 
 
 
 
 
  
 
 
 
  
 
 
  
Human influenza viruses, such as the 2009 pandemic H1N1 virus, recognize and 
bind to human α-2,6–linked sialic acid receptors in the upper respiratory tract.  Avian 
influenza viruses, such as H5N1, predominantly recognize α-2,3–linked sialic acid 
receptors in the human lower respiratory tract.  The human H7N9 influenza virus is 
unusual in recognizing both types of receptors and, therefore, has the possibility of 
sustained human-to-human transmission and pandemic potential7.   
6.2 
Review of investigational medicinal product 
6.2.1 
Neumifil 
 
 
 
 
 
 




Safety and tolerability of single and repeated Neumifil 
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6.2.3 
Safety pharmacology 
A functional observation battery was used to assess neurotoxicity of Neumifil in a 
28-day study in rats.  No neurotoxicity was observed after repeated doses up to 
1040 µg/animal/day, although a slight increase in the presence of pinna reflex was 
seen in both male and female treated animals.  In a functional observation battery in 
primates Neumifil had no significant central nervous system (CNS) effects at 
repeated doses up to 1.65 mg/kg/day for 28 days.   
Cardiovascular safety of Neumifil was tested in a 28-day repeat dose study in 
Cynomolgus monkeys.  Animals received repeated doses up to 1.25 mg/kg/day, and 
there were no changes in ECG, or in diastolic and systolic blood pressure. 
Standalone respiratory safety studies have not been done.  The pharmacology of 
Neumifil does not suggest any respiratory risk, and no significant lung pathology has 
been noted in efficacy studies in mice and rats, or in dose-finding studies.  Specific 
respiratory observations were made during the 28-day repeat dose study in primates.  
There were no changes in respiratory signs (rhinorrhoea, sneezing, coughing, 
abnormal breath sounds, respiratory rate, and breathing depth). 
6.2.4 
Pharmacokinetics 
The absorption and pharmacokinetics of Neumifil have been studied after single 
intravenous and intranasal doses in rats.  Neumifil 0.5 mg/kg given intravenously 
yielded mean Cmax 1240 ng/mL, AUC(0-inf) 2360 ng.h/mL, and terminal half-life 
24.1 h (range 9.29–46.0 h).  Pharmacokinetic parameters could not be calculated 
after intranasal administration of 4 mg/kg Neumifil, because plasma concentrations 
were above the lower limit of reliable quantification (LRQ: 25.0 ng/mL) in only a 
single sample at 2 h post dose (plasma concentration 42.8 ng/mL).  Bioavailability of 
intranasal Neumifil was therefore considered to be < 5%. 
Very low plasma concentrations of Neumifil were detected during the 28-day 
repeated dose study in rats.  The paucity of samples with quantifiable concentrations 
of Neumifil precluded any calculation of (pharmacokinetic) PK parameters, but 
systemic exposure was clearly minimal after repeated intranasal administration of 
doses up to 1040 µg/day.  Given the low plasma concentrations of Neumifil after 
intranasal dosing, its distribution has not been studied. 
It is anticipated that intranasal Neumifil (a protein) will be broken down in the nasal 
mucosa by local peptidases to yield oligopeptides and free amino acids.  Thus, 
further investigation of Neumifil metabolism is deemed unnecessary. 


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6.2.5 
Toxicology 
In the rat dose-range finding study, systemic exposure to Neumifil could not be 
determined because too few plasma samples had concentrations above LRQ.  Rats 
received intranasal doses up to 1000 µg/day for 7 days, and there were no treatment-
related deaths or significant clinical observations.  However, some female rats had a 
slight decrease in body weight gain (average 3%), attributed to decreased food 
consumption.  The maximum tolerated dose was 1000 µg/animal/day.  
In the pivotal Good Laboratory Practice (GLP) 28-day repeated dose toxicity study 
in rats, animals received intranasal doses of 520, 780, and 1040 µg/animal/day, but 
again few samples had plasma Neumifil concentrations above LRQ.  The following 
pharmacokinetic parameters were estimated for Day 28:  Cmax 123 ng/mL; tmax 2 h; 
and AUC 381 ng.h/mL.  No animal died, but significant weight loss occurred at the 2 
highest dose levels (6% in males and 7% in females).  That adverse effect was 
reversible after 2 weeks’ recovery.  Abnormal respiratory sounds (loud breathing 
and/or respiratory crackles) were observed at all dose levels but remitted after dosing 
was stopped.  Mild to moderate inflammatory and reactive changes in the nasal 
mucosa, associated with polymorphonuclear cell infiltration and goblet cell 
proliferation, were found in all treatment groups but were considered adverse only 
the at the mid and top dose levels.  Inflammatory changes were noted also in 
respiratory tissues (larynx, trachea, bronchi and bronchioles) at the 2 highest dose 
levels of Neumifil, but animals recovered fully after 2 weeks.  The no observed 
adverse effect level (NOAEL) in rats after 4 weeks’ dosing was 2.5 mg/kg/day.   
In a non-GLP dose-range finding study, Cynomolgus monkeys received doses up to 
1.25 mg/kg/day for 7 days.  There were no treatment-related deaths or significant 
clinical findings.   
Doses of 0.8, 1.20 and 1.65 mg/kg/day were tested in a GLP 28-day repeated dose 
Cynomolgus monkey toxicity study.  All plasma concentrations of Neumifil were 
below LRQ.  There were no deaths, and no effects related to the test item.  ADA 
analysis showed weak seroconversion in 4 animals, but ADA titres were similar to 
those in untreated animals, so Neumifil was of low immunogenicity.  The NOAEL in 
Cynomolgus monkeys after 4 weeks’ dosing was 1.65 mg/kg/day. 
6.2.6 
Pharmacodynamics 
Doses of up to 100 µg Sp2CBMTD were administered to BALB/c mice in order to 
investigate the potential mechanism of action of the parent family of HEX17, and its 
efficacy in preventing and treating infection with the influenza virus.  Sp2CBMTD 
was either administered prophylactically to mice that were then challenged with a 
lethal dose of the virus, or administered after the viral challenge.  As well as 
promoting animal survival (80–100% when administered prophylactically, or 40% 
after exposure to the virus), cytokine analysis revealed that Sp2CBMTD stimulated a 
proinflammatory response when given as a prophylactic.  
 


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  Neumifil has low to minimal risk of generating viral 
resistance because of its host- and viral-targeting modes of action.  Neumifil’s in 
vitro and in vivo animal data, potential pan-viral efficacy, and toxicology profile 
makes it suitable for progression to a FTIH study.  
6.3 
Rationale for the trial 
This FTIH study will investigate the safety and tolerability of Neumifil after single 
and repeated intranasal administration in a randomised, double-blind, placebo-
controlled trial.   The results of this study will be used to select doses for subsequent 
trials.  
6.4 
Rationale for choice of dose(s) 
6.4.1 
Starting dose 
In the absence of the viral target, the minimum anticipated biological effect level 
(MABEL) is not relevant in calculating the starting dose.  Instead, the safety-focused 
no observed adverse effect (NOAEL) approach was used.   
As is typical for molecules dosed intranasally8, the margin of safety was calculated 
based on both systemic and local toxicity.  The Human Equivalent Dose (HED) was 
not corrected for body surface area, as HEX17 is a recombinant protein of molecular 
weight 162 kD, and proteins are typically normalised on a mg/kg basis without 
allometric scaling.   
The NOAELs in the 28-day GLP toxicology studies in rats and Cynomolgus 
monkeys were 2.5 mg/kg/day and 1.65 mg/kg/day, respectively.  The monkey is the 
more sensitive species and is also the more relevant for humans with respect to nasal 
structure and toxicity9, so was used to calculate safety margins.  The margins of 
safety for the planned first dose and maximum intended clinical dose, calculated for 
systemic toxicity (mg/kg/day) and local toxicity (mg/kg/cm2) are shown, 
respectively, in Table 1 and Table 2.    
 
 




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Protocol Version 3, dated 15 December 2021   
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The doses to be tested in Part B will be selected by the SRG as describe in section 
8.5.1.  
The top dose will not exceed 2.8 mg 
6.5 
Assessment and management of risk 
Any safety risk to study participants is mitigated by the following considerations. 
• Data from pre-clinical studies suggest that Neumifil is devoid of any significant 
CNS or cardiovascular effects.  Although standalone respiratory safety studies 
have not been performed, the pharmacology of Neumifil does not suggest any 
respiratory risk, and no significant lung pathology has been noted in efficacy 
studies in mice and rats, or in dose range finding studies. 
• In the pivotal GLP 28-day repeated dose toxicity study in rats, significant weight 
loss was observed in animals at the two highest dose levels:  780 and 
1040 µg/animal/day (6% in male and 7% in female animals).  This adverse effect 
was found to be reversible after 2 weeks recovery.  
• Abnormal respiratory sounds (loud breathing and/or respiratory crackles) were 
observed at all doses levels, and this ceased after dosing was stopped.   
• Mild to moderate inflammatory and reactive changes were found in the nasal 
mucosa and respiratory tissues, in animals receiving the two highest dose levels 
of Neumifil, although animals fully recovered after 2 weeks.  The NOAEL in rats 
following 4 weeks of dosing was 2.5 mg/kg/day.   
• The available pre-clinical toxicity data indicate an acceptable safety profile for 
Neumifil.  The NOAEL in the Cynomolgus monkey corresponds to a HED of 
0.46 µg in humans with a body weight of 60 kg.  The proposed starting dose in 
Part A of 0.028 mg provides a 3587 fold and 10,600 fold margin of safety based 
on bodyweight or when normalised by nasal surface area respectively.  The 
maximum selected dose provides a 112 and 331 fold margin of safety when 
calculated according to bodyweight, or when normalised by nasal surface area, 
respectively.  In addition, the starting dose selected for Group B1 in Part B 
(multiple ascending dose part of the study) will be no higher than the highest 
dose that caused no safety concerns in Part A. 
• Dose escalation will take place only after safety and tolerability data from 
preceding dose level(s) have been reviewed.  There will be an appropriate 
interval between sequential groups, to allow for review of those data.  Dose 
escalation will be halted if the stopping criteria are met (see section 8.4.2).  
• As Neumifil has never been given to humans before, each new ascending dose 
will be staggered:  sentinel subject will be dosed first, and the remaining subjects 
will be dosed at least 23 h later. 
• If the dose level selected is no higher than one that has already been shown to 
cause no safety concerns, sentinel subjects will not be required, and subjects will 
be dosed at intervals of at least 10 min.  The maximum dose will not exceed 
2.8 mg. 
• As this is a first-in-human study, the investigator must obtain a reply from the 
GP, or have a valid GP reply on file, before dosing a subject (Part A). 


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• Only subjects who are identified as healthy in respect of major organ classes, as 
assessed by their medical history, and clinical and laboratory variables will be 
included in the study.  
• Subjects with presence or history of respiratory disease will be excluded from the 
study.  Respiratory function will also be assessed in the form of spirometry at 
screening. 
• Subjects will be monitored frequently throughout the study for safety and 
tolerability.  The safety monitoring practices employed by this protocol are 
adequate to protect the subjects’ safety and should detect all expected treatment 
emergent adverse events (TEAEs). 
• HMR is accredited by the Medicines and Healthcare products Regulatory Agency 
(MHRA) to do first-in-human studies and will follow its standard operating 
procedures (SOPs). 
• HMR maintains its own resuscitation team (SOP SS329) to deal with medical 
emergencies, including anaphylaxis and cardiac arrest.  The team will be on duty 
continuously, until at least 24 h after each dose. 
• Any risks are adequately mitigated by safety assessments, and by the medical 
cover provided by the investigator site, and by appropriate IMP manufacture, 
according to Good Manufacturing Practice (GMP).  
• There will be no direct health benefit for study participants from receipt of study 
medication.  An indirect health benefit to the healthy subjects enrolled in this trial 
is the free medical examination received at screening and during the study. 
• The overall risk benefit balance is considered to be acceptable.  
6.5.1 
Conducting the trial during the COVID-19 pandemic 
The principal investigator and sponsor have reviewed the risks of conducting the trial 
in light of the current COVID-19 pandemic.  The first priority is the safety of trial 
subjects and staff, but we also have an ethical duty to preserve the scientific integrity 
of the trial as far as possible. 
Neumifil is a potential medication against SARS-CoV-2 infection, although this 
study is in healthy volunteers and no benefit is expected.  Preliminary non-clinical 
data indicate that Neumifil can protect recipient animals (Syrian hamster) against 
infection by SARS-CoV-2 and therefore no specific risks to participants due to 
conducting the study during the COVID-19 pandemic are anticipated.  Non-clinical 
work in mice, has shown that pre-treatment of mice with Neumifil, before a lethal 
influenza challenge, protects mice from the viral challenge and does not reduce the 
development of protective immune responses against the influenza strain.  Therefore, 
it is not anticipated that Neumifil will attenuate the immune response to a vaccine.  
No interaction between Neumifil and vaccinations against COVID-19 are 
anticipated. 
The purpose of this study is to assess safety and tolerability of Neumifil; to avoid an 
overlap of adverse events, the administration of Neumifil will not be within 7 days of 


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Protocol Version 3, dated 15 December 2021   
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a vaccination against COVID-19.  Subjects will be resident in the HMR Phase 1 unit 
for the dosing period.  Avoiding administering Neumifil within 7 days of a 
COVID-19 vaccination will mean subjects in Part A will have a 14-day window 
(Day –7 to Day 8 with dosing on Day 1) when they will not be eligible for the study 
if they have a COVID-19 vaccination booked.  In Part B there will be a 21-day 
window (Day –7 to Day 15 with dosing on Day 1) when they will not be eligible for 
the study if they have a COVID-19 vaccination booked. 
This clinical trial will be done in accordance with HMR’s COVID-19 risk mitigation 
policy (RMP), which documents HMR’s COVID-19 virus testing strategy for 
volunteers and staff, social distancing measures, and management of COVID-19-like 
symptoms.  HMR’s RMP was first notified to the MHRA and Health Research 
Authority (HRA) on 22 May 2020, and applies across all HMR’s trials.  The 
mitigation measures specified in the HMR COVID-19 RMP are deemed adequate for 
this trial.  Any deviations from the RMP will be documented in a separate 
COVID-19 trial-specific risk assessment, prepared by the investigator.  Any 
deviations from the protocol that result from the COVID-19 pandemic, and 
COVID-19 related AEs or SAEs, will be documented. 
Taking the above factors into account, and the proposed mitigation, we believe that it 
is medically and ethically acceptable to proceed with the trial during the current 
COVID-19 pandemic. 
7 
Objectives and endpoints 
7.1 
Objectives 
7.1.1 
Primary objectives 
Part A 
• To assess the safety and tolerability of single-ascending intranasal doses of 
Neumifil in healthy subjects. 
Part B 
• To assess the safety and tolerability of multiple-ascending intranasal doses of 
Neumifil in healthy subjects. 
7.1.2 
Exploratory objective 
• To determine the number of subjects contracting SARS-CoV-2 during the 7 days 
after receiving their (last) dose. 
• To assess the formation of Neumifil ADAs after multiple-ascending intranasal 
doses in healthy subjects (Part B only). 


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• 
To assess the plasma concentration of single- or multiple-ascending intranasal 
doses of Neumifil in healthy subjects to determine if intranasal administration 
results in systemic exposure. 
• 
To assess the concentrations of cytokines and chemokines in nasal secretions 
before dosing and after multiple intranasal doses of Neumifil (Part B only). 
7.2 
Endpoints 
7.2.1 
Primary endpoints 
Safety and tolerability:   
Clinically significant changes in:  vital signs (heart rate, blood pressure, respiratory 
rate, pulse oximetry and temperature), 12-lead ECG, FEV1, FVC, physical 
examination, nasal examination, laboratory safety tests (haematology, biochemistry 
and urinalysis), tolerability questionnaire, AEs and serious AEs (SAEs).  Safety 
endpoints will be assessed up to 7 days after dosing in Part A or up to 14 days after 
the last dose in Part B. 
7.2.2 
Exploratory endpoint 
Safety:  SARS-CoV-2 infection test, done at screening, before the first dose, on Day 
8 (Part B only), and at follow-up.  
Immunogenicity:  ADAs of Neumifil, as assessed by IgA and IgG concentration, 
derived from blood samples taken before the first dose and at Follow-up (Part B 
only). 
Plasma concentration of Neumifil:  Plasma concentrations of Neumifil after single 
doses on Day 1 in Part A, and after dosing on Days 1 and 7 in Part B.  
Cytokine and chemokine concentrations in nasal secretions:  Presence and 
concentration of cytokines and chemokines, measured by multiplex assay, in nasal 
wick samples collected on Day –1, Day 8, and at follow up (Part B only).  
8 
Overall trial design 
8.1 
Trial design 
This is a Phase 1, single-centre, randomised, placebo-controlled FTIH study in 
healthy subjects.  The study is in 2 parts and will investigate single-ascending 
(Part A) and multiple-ascending (Part B) doses of Neumifil, administered 
intranasally.  
Schematic diagrams of the study design are in section 8.2. 


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8.1.1 
Part A 
Enrolment of up to 36 healthy subjects is planned, in up to 5 groups 
(Groups A1−A5).  Groups A1–A3 will consist of 6 subjects each, and Groups A4 
and A5 will consist of 9 subjects each.   
Subjects will receive a single intranasal dose of Neumifil or placebo.  In 
Groups A1−A3, 4 subjects will receive Neumifil and 2 will receive matching 
placebo.  In Groups A4 and A5, 6 subjects will receive Neumifil and 3 will receive 
matching placebo.  Additional dose levels may be explored in up to 2 optional groups 
of up to 9 subjects each.  
The starting dose for Group A1 is 0.028 mg Neumifil.  Subsequent planned doses are 
given in Table 3.  
Table 3  
Planned doses in Part A 
Group 
Planned nominal 
dose of Neumifil 
Number of 
subjects 
Number on 
placebo 
A1 
0.028 mg 
6  
2 
A2 
0.085 mg 
6 
2 
A3 
0.28 mg 
6 
2 
A4 
0.885 mg 
9 
3 
A5 
2.8 mg 
9 
3 
A6 (optional) 
To be decided 
9 
3 
A7 (optional) 
To be decided 
9 
3 
Because Neumifil has never been given to humans before, each new ascending dose 
will be staggered:  sentinel subjects will be dosed first, and the remaining subjects 
will be dosed at least 23 h later.  To maintain the blind nature of the study, the 
2 sentinel subjects will be randomised to ensure that 1 subject receives active 
treatment and the other receives placebo.  Since 1 subject will receive placebo 
treatment, the sentinel subjects may be dosed at least 5 min apart.  Provided the 
investigator considers the safety and tolerability in the sentinel subjects to have been 
acceptable, the remaining subjects will be dosed, at intervals of at least 10 min. 
The planned dose levels may be changed, depending on the safety and tolerability 
results after previous doses, as described in section 8.5.  The dose will not be 
escalated unless the safety and tolerability of the previous dose is acceptable.  There 
will be an appropriate interval between sequential groups, to allow for review of 
those data.  If the dose level selected is no higher than one that has already been 
shown to cause no safety concerns, sentinel subjects will not be required, and 
subjects will be dosed at intervals of at least 10 min.  The maximum dose will not 
exceed 2.8 mg. 


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Protocol Version 3, dated 15 December 2021   
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Subjects will be screened within 35 days before their dose of trial medication.  
Subjects will be resident on ward from 1 day before their dose (Day –1) until about 
24 h after dosing (Day 2).  They will return for a follow-up visit 7–8 days after their 
dose (Day 8–9). 
8.1.2 
Part B 
Enrolment of up to 24 healthy subjects is planned, in up to 3 groups of 8 subjects 
(Groups B1−B3).   
Subjects will receive once-daily intranasal doses of Neumifil or placebo for 7 days.  
In each group, 6 subjects will receive Neumifil and 2 will receive matching placebo.      
Part B can start before completion of Part A.  The starting dose level (dose and dose 
regimen) for Group B1 will be decided after review of safety and tolerability data 
from at least 3 dose levels in Part A, and will be no higher than a dose that has 
previously been shown to cause no safety concerns in Part A (see section 8.5.3).  An 
additional dose level may be explored in 1 optional group of up to 8 subjects (Group 
B4).  Subsequent doses levels, including maximum duration of dosing, will be 
determined as described in Part A.   
Subjects will be screened within 35 days before their dose of trial medication.  
Subjects will be resident on ward from 1 day before their dose (Day –1) until about 
24 h after their last dose (Day 8).  Subjects will attend an outpatient visit at 7−8 days 
after their last dose (Days 15–16).  They will then return for a follow-up visit at 
13−15 days after their dose (Days 21–23). 


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8.2 
Study flow chart 
Figure 3 
Study flow chart 
 
OP:  outpatient visit.  Part B can start after review of safety and tolerability data from at least 3 dose levels in Part A.  Groups A6, A7 
and B4 are optional.  Dose selection for Part A and B is described in section 8.5.2 and 8.5.3.  


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8.3 
Definition of the end of the trial 
The end of the trial is defined as the final follow-up visit by the last subject.  If the 
trial is terminated prematurely, the trial ends when the sponsor notifies the 
investigator in writing that the trial has finished, or when the last subject attends the 
final follow-up visit, whichever is later.   
8.4 
Stopping criteria 
8.4.1 
Trial stopping criteria 
The trial will be stopped if either of the following occurs: 
• one or more SAEs considered to be at least possibly related to study treatment; or 
• 2 or more severe or clinically significant AEs considered to be at least possibly 
related to study treatment at any dose level. 
Treatment allocations may be unblinded to aid safety review, provided that the 
unblinding is appropriately documented.   
If, after an internal safety review, it is appropriate to restart the trial, a substantial 
amendment will be submitted to the MHRA and research ethics committee (REC).  
The trial will not restart until the amendment has been approved by the MHRA and 
REC. 
8.4.2 
Dose escalation stopping criteria 
A dose level will not be repeated, or exceeded, if either of the following apply: 
• the results of safety tests give the sponsor or investigator cause for concern 
• the investigator or sponsor considers that dose level to be poorly tolerated 
The trial will be stopped if any criterion in section 8.4.1 is met. 
See section 9.4 for individual subject withdrawal criteria.  Dosing will be 
discontinued in an individual if any criterion in section 9.4 is met. 
8.5 
Criteria for dose selection 
8.5.1 
Review of data by the SRG 
During the study, the dose level (dose and [if applicable] dose regimen) will be 
increased only if the safety and tolerability of the previous dose level is acceptable. 
All dose levels will be selected by the SRG, which will include (as a minimum) the 
principal investigator (or delegate) and the sponsor’s medically qualified 


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representative (or delegate).  Each dose decision will be made and documented in 
line with HMR SOPs. 
Before confirming the dose level for any group, the SRG will review, as a minimum, 
safety and tolerability data from the previous dose level and (if different) the highest 
dose level tested to date, as described below.  Safety and tolerability data obtained 
from the previous group(s) will also be reviewed, if applicable.  All data used to 
support dose selection will be quality checked.   
Review of safety and tolerability data 
The SRG will review (as a minimum) safety and tolerability data, up to 7 days after 
(final) dosing, from at least 4 evaluable subjects who have received active treatment 
at the highest dose level tested to date.  An evaluable subject is one who completes 
dosing, has undergone procedures until 7 days after (final) dosing, and has no major 
protocol deviations.  To maintain blinding, data from at least 6 subjects in each group 
of 6 (Groups A1–A3) or 8 (Groups B1–B3), or from at least 7 subjects in each group 
of 9 (Groups A4 and A5), must be reviewed to ensure that the dataset includes at 
least 4 evaluable subjects on active treatment.  If fewer subjects than planned are 
dosed, any subjects required to complete the group may be dosed in parallel with 
subsequent groups.   
The safety data reviewed will include, as a minimum:  
• AEs and SAEs, including description, intensity, onset, duration, and relationship 
to treatment 
• vital signs  
• 12-lead safety ECG 
• laboratory safety tests 
• physical examination 
• nasal examination 
• FEV1 
• tolerability questionnaire 
Review of pharmacokinetic data 
It is not expected that a review of the PK will form part of the dose escalation 
decision, as the plasma concentrations are expected to be very low/not detectable.  
However, if PK data are reviewed, dummy-subject identifiers will be applied to the 
data by the bioanalytical laboratory, or an unblinded programmer at HMR, so that 
individual data may be reviewed without unblinding the investigator or any blinded 
sponsor representatives.  If fewer subjects are dosed than planned, to avoid potential 
unblinding, individual data will not be reviewed – mean, minimum and maximum 
data will be reviewed, and number of subjects will not be presented.  If there are 
missing PK data at a particular timepoint, the missing data may be replaced by an 
interpolated value to maintain blinding.   
 


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8.5.2 
Dose selection for Part A 
Planned dose levels in Part A (Table 3) may be changed based on emerging data.   
It is expected that the dose level will be increased for each group (Groups A1–A5).  
The dose will be increased such that it does not exceed 3.5-times the highest dose 
level that was safe and well tolerated.  
Two further dose levels may be explored in the optional groups of subjects (Groups 
A6 and A7).  No dose will exceed 2.8 mg.  The trial will be stopped if the criteria in 
section 8.4.1 are met. 
The scheduled dose of Neumifil may be reduced if, for example, the results of safety 
tests give us cause for concern, or tolerability is poor.   
8.5.3 
Dose selection for Part B 
Part B will not proceed until the SRG has reviewed safety and tolerability data (up to 
7 days after dosing) from at least 3 dose levels in Part A, as described in 
section 8.5.1.   
The first total daily dose level (dose and dose regimen [ie once- or twice-daily]) to be 
tested in in Part B will be the same as, or lower than the highest single dose level that 
has been given in Part A without any safety concerns.  For subsequent groups in Part 
B, the dose level will be escalated only if the safety and tolerability of the previous 
dose level are acceptable and do not exceed the highest single dose tested in Part A 
that caused no safety concerns. 
The planned duration of dosing (7 days) may be changed based on emerging data but 
will not exceed 14 days.   
8.5.4 
Repeating a dose level or selection of a lower dose level (Parts A and B) 
In Parts A and B, it is expected that the dose will be increased for each group.   
The SRG may decide to test a lower dose level of Neumifil, or to repeat a dose level, 
provided it does not meet any of the criteria in Section 8.4.  Such decisions will be 
made and documented in line with HMR SOPs.  A dose level may be repeated under 
the following circumstances. 
• If it was safe and well tolerated.  
• If AEs occur that cause mild or moderate discomfort, but do not in any way 
threaten the health of the subject, that dose level may be repeated with the aim of 
exploring further the relationship between dose and AE.  If, in the SRG’s 
judgement, it would be unreasonable to expose further subjects to the level of 
discomfort experienced by the subjects who have already received the dose, a 
lower dose may be tested.  The selected dose will be either a lower dose level that 
has already been given, or an intermediate level that has not previously been 


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given; in either case, the aim is to learn more about the relationship between AEs 
and dose of Neumifil. 
9 
Trial population 
9.1 
Planned number of subjects 
Up to 60 healthy volunteers (up to 36 in Part A and up to 24 in Part B), excluding 
replacements and optional groups.  
9.2 
Inclusion criteria 
1. Healthy male or female volunteer, aged 18–60 years.  
2. BMI (Quetelet index) in the range 18.0–30.9 kg/m2.  
Body Mass Index  = 
   
3. Able to understand the nature of the trial and any hazards of participating in it.  
Ability to communicate satisfactorily with the investigator and to participate in, 
and comply with the requirements of, the entire trial. 
4. Willingness to give written consent to participate after reading the information 
and consent form, and after having the opportunity to discuss the trial with the 
investigator or their delegate.  
5. Agree to follow the contraception requirements of the trial as described in 
section 11. 
6. Agree not to donate blood or blood products during the study and for up to 
3 months after the administration of the trial medication. 
7. Spirometry readings (FEV1 and FVC) to be ≥ 80% of predicted value at the 
screening visit, calculated using National Health and Nutrition Examination 
Survey (NHANES) reference.  If a subject’s FEV1 or FVC is outside that range 
at the screening visit, the test may be repeated once on another day. 
8. Registered with a General Practitioner (GP) in the UK (Part A only). 
9. Willingness to give written consent to have data entered into The 
Overvolunteering Prevention System (TOPS). 
9.3 
Exclusion criteria 
1. Woman who is pregnant or lactating, or pre-menopausal woman who is sexually 
active and not using a reliable method of contraception (see section 11). 
2. Clinically relevant abnormal medical history, physical findings, ECG, or 
laboratory values at the pre-trial screening assessment that in the opinion of the 
weight [kg]
(height [m])2


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investigator could interfere with the objectives of the trial or the safety of the 
volunteer.   
3. Presence or history of acute or chronic illness sufficient to invalidate the 
volunteer’s participation in the trial or make it unnecessarily hazardous. 
4. Presence or history of respiratory disease, including (but not limited to) asthma, 
chronic obstructive pulmonary disease (COPD), cystic fibrosis, emphysema, 
requiring acute or chronic medication. 
5. Presence of nasal polyps or significant nasal abnormalities.  
6. Symptoms of respiratory illness (including, but not limited to, runny nose, sore 
throat, sneezing, coughing or wheezing) at the screening visit or before dosing 
on Day 1. 
7. Tympanic temperature > 37.5°C at the screening visit or before dosing on Day 1. 
8. Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes 
mellitus, coronary heart disease, or history of any psychotic mental illness. 
9. History of psychiatric disease, as determine by the investigator. 
10. History or presence of malignant disease. 
11. Immune-suppressed status, resulting from either disease or medication, as 
determined by the investigator.  
12. Presence or history of severe adverse reaction to any drug or the excipients of 
Neumifil.  
13. Known allergy to tetracycline antibiotics. 
14. Use of a prescription medicine (except HRT in female subjects), including oral 
contraceptives, during the 28 days before the first dose of trial medication, or use 
of an over-the-counter medicine, with the exception of acetaminophen 
(paracetamol) and vitamin or nutritional supplements, during the 7 days before 
the first dose of trial medication. 
15. Receipt of an investigational product (including prescription medicines) as part 
of another clinical trial within the 3 months before admission to this study; in the 
follow-up period of another clinical trial at the time of screening for this study. 
16. Receipt of a COVID-19 vaccine within 7 days before the first dose of trial 
medication, or anticipate receiving a COVID-19 vaccine within the 7 days after a 
(final) dose of trial medication.  
17. Presence or history of drug or alcohol abuse, or regular intake of more than 
14 units of alcohol weekly. 
18. Use of cigarettes or nicotine-containing products during the 6 months before first 
dose of trial medication.  


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19. Blood pressure and heart rate in supine position at the screening examination 
outside the ranges:  blood pressure 90–140 mm Hg systolic, 40–90 mm Hg 
diastolic; heart rate 40–100 beats/min.  Triplicate measurements will be made (at 
least 2 min apart), and a mean value outside the above ranges will lead to 
exclusion.   
Repeat measurements (in triplicate) are permitted if values are borderline (ie 
values that are within 5 mm Hg for blood pressure or 5 beats/min for heart rate) 
or if requested by the investigator.  Subjects can be included if the repeat value is 
within range or still borderline but deemed not clinically significant by the 
investigator.     
20. QTcF value, of > 450 msec (men) or > 470 msec (women); or QRS duration 
≥ 120 msec, measured on 12-lead ECG at the screening visit.  Triplicate 
measurements will be made, and a mean value used to determine eligibility.  A 
repeat (in triplicate) is also allowed on one occasion for determination of 
eligibility.   
21. Possibility that the volunteer will not cooperate with the requirements of the 
protocol. 
22. Positive test for hepatitis B surface antigen, hepatitis C or HIV.  NOTE:  
participants with positive hepatitis C antibody owing to resolved disease can be 
included only if a hepatitis C ribonucleic acid (RNA) test is negative. 
23. Positive test for SARS-CoV-2 (polymerase chain reaction; PCR) or suspected 
exposure to the SARS-CoV-19 virus during the 14 days before screening.  
24. Loss of more than 400 mL blood during the 3 months before the trial, eg as a 
blood donor. 
25. Objection by GP to volunteer entering trial. 
9.4 
Withdrawal of subjects from the trial 
9.4.1 
Withdrawal of subjects 
Subjects are free to withdraw from the trial at any time without giving reasons.  
Furthermore, the investigator may withdraw a subject for reasons such as intolerance 
to trial medication, intercurrent illness, need for medication, which is 
contraindicated, significant non-compliance with the requirements of the trial, or 
withdrawal of consent.  The investigator will assess the reasons for withdrawal as far 
as possible and will fully record the circumstances and medical details. 
9.4.2 
Individual subject stopping criteria (Part B only) 
A subject who meets any of the following criteria will receive no further doses. 
• SAE considered related to study treatment. 


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• alanine aminotransferase (ALT) ≥ 5 x the upper limit of normal (ULN). 
• ALT ≥ 3 x ULN and total bilirubin ≥ 2 x ULN or international normalised ratio 
(INR) of ≥1.5, as per the guidelines for acute liver failure (if a subject meets that 
withdrawal criterion, serum bilirubin fractionation should be performed).  
• ALT ≥ 3 x ULN if associated with the appearance or worsening of rash or 
hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia).  Subjects who have ALT ≥ 3 x ULN and 
< 5 x ULN, and total bilirubin < 2 x ULN, who do not exhibit hepatitis symptoms 
or rash, can continue in the study (and continue receiving trial medication) as 
long as they can be monitored weekly until liver chemistries return to within 
baseline values. 
• FEV1 or FVC of < 80% predicted or a decrease of > 20% from baseline 
• Peripheral arterial oxygen saturation (SpO2) of < 94% 
Subjects who meet the above criteria will be considered discontinued from dosing.  
However, the investigator may ask the subject to continue their participation in the 
study so they can be monitored for safety, PK and immunogenicity, or the 
investigator may withdraw the subject from the trial. 
Subjects will be informed before they agree to take part in the trial that, if they 
withdraw or are withdrawn: 
• the investigator will stop collecting information about them; and  
• they can ask the investigator to destroy any identifiable samples taken from them.  
The investigator will ask withdrawn subjects to provide written consent to a follow-
up examination, to check that they have come to no harm as a result of taking part in 
the trial.  Provided that the subject agrees, they will undergo, at withdrawal from the 
trial (or as soon as possible afterwards), the standard medical examination and 
laboratory tests which they would have undergone had they completed it.  The 
investigator will record in the case report form (CRF) the results of the follow-up 
examination of withdrawn subjects, if they give their consent for that. 
9.4.3 
Replacement of withdrawn subjects 
Withdrawn subjects will be replaced at the discretion of the sponsor and investigator.  
Replacements for withdrawn subjects will receive the treatment(s) intended for the 
withdrawn subject.   
10 
Treatments 
10.1 
Treatments administered 
Part A:  subjects will receive a single dose of Neumifil or placebo.  


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Part B:  subjects will receive once-daily doses of Neumifil or placebo for 7 days. 
All doses will be administered intranasally using an Aptar liquid delivery system.  
Each dose will consist of nasal drops/spray administered as a maximum volume of 
0.5 mL to each nostril.  Subjects must lie supine for 5 min after dosing.  Further 
details will be provided in a separate manual.   
Fasting requirements are described in section 11.  
10.2 
Overdose 
Symptoms of overdose of Neumifil are not yet known. In the case of accidental 
overdose, subjects should be treated symptomatically as no specific antidote is 
available. 
10.3 
Blinding 
The trial medication will be repackaged and relabelled by the HMR Pharmacy, 
according to the randomisation schedule.  Active and placebo treatments will be 
labelled such that it is not possible to distinguish between them.  If the expiry dates 
of placebo and active treatment differ, both treatments will be labelled with an expiry 
date no later than the earlier of the 2 expiry dates.  Each subject’s treatment will be 
given a unique code number, traceable to the batch number of the medication.   
The placebo and active treatments for each group will be identical in appearance, and 
similar in taste and smell.  To maintain the blind nature of the trial, in each group, the 
number of sprays of placebo treatment will be the same as active treatment.  
A sealed copy of the randomisation code will be kept in a locked file in the HMR 
Pharmacy.  A copy will also be kept by the bioanalytical laboratory.  The 
investigator will be supplied with sealed envelopes, each one containing the 
treatment allocation for the subject whose number appears on the outside of the 
envelope.  Those envelopes will be kept in the trial master file, readily accessible to 
clinical staff.  Sealed individual code break envelopes will also be provided to the 
Pharmacovigilance Service Provider.   Emergency procedures for revealing 
medication codes are specified in section 10.4.   
The investigators, medical monitor and clinical monitor will remain blinded 
throughout the trial, unless safety concerns necessitate unblinding (see section 10.4 
below).   
10.4 
Unblinding procedure 
If unblinding is required in the interest of the safety of a subject (for example, in a 
medical emergency where the identity of the investigational material will affect the 
management of the subject), the principal investigator or delegate will open the 
individual code-break envelope for that subject without prior consultation with the 




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Replacements for withdrawn subjects will be given a number equal to that of the 
subject that they replaced plus 100.  So, Subject 1001 would be replaced by 
Subject 1101, and Subject 2025 would be replaced by Subject 2125, and so on. 
10.6 
Selection and timing of dose for each subject 
The treatments to be administered are described in sections 8.1 and 10.1.  Subjects 
will be randomly assigned to those treatments, as described in section 10.5 above.   
Because Neumifil has never been given to humans before, each new ascending dose 
in Part A will be staggered as described in section 8.1. 
In Part A, all doses will be given in the morning.  In Part B, doses will be given once 
or twice-daily at the same time each day (± 15 mins from the time of dosing on Day 
1).  
10.7 
Previous and concomitant treatment 
Restrictions on previous medication are described in exclusion criterion 14. 
During the trial, concomitant medication may be given if the subject’s GP believes it 
to be necessary.  In addition, up to 4 doses of 500 mg paracetamol will be allowed 
per day for mild analgesia.  No COVID-19 vaccine is allowed during the 7 days 
before the first dose of trial medication or the 7 days after the final dose of trial 
medication.  Any other concomitant treatment will be given only if deemed strictly 
necessary by the investigator or co-investigator.  In any case, all concomitant 
treatments will be reported in the CRF along with their daily dosage, duration, route 
of administration, and reasons for administration.  Subjects who have received any 
concomitant treatment may be withdrawn from the trial at the discretion of an 
investigator. 
10.8 
Assessment of compliance 
Subjects will be dosed on the research ward under the supervision of 2 suitably 
trained members of HMR staff.  
11 
Dietary and lifestyle restrictions 
Subjects will abide by HMR house rules while on the ward.   
Part A 
Subjects will fast (no food or drink other than water) overnight for ≥ 8 h before 
dosing until 2 h after dosing on Day 1.  Standard meals will be provided at about 2, 4 
and 10 h after dosing.   


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Part B 
Morning dose:  Subjects will fast (no food or drink other than water) overnight for 
≥ 8 h before dosing until 2 h after dosing on Day 1 and Day 7.  Standard meals will 
be provided at about 2, 4 and 10 h after dosing on Day 1 and Day 7.   
Evening dose (if applicable):  Subjects will fast (no food or drink other than water) 
for at least 2 h before and 2 h after dosing on Day 1 and 7. 
At all other times during the study, standard meals will be given at usual times.   
All study parts 
During the study, subjects will fast for at least 8 h before laboratory safety blood 
samples are taken at screening, on admission (Day –1), and Follow-up. 
No alcoholic drinks or smoking will be allowed during the period from 24 h before 
admission until follow-up.  No caffeinated drinks will be allowed from 24 h before 
admission until discharge from the ward (Day 2 in Part A and Day 8 in Part B).  No 
strenuous exercise will be allowed from 2 days before screening until follow-up.   
Subjects will rest in bed in the supine position during and until ≥ 5 min after dosing. 
Subjects must not sunbathe or use a sunbed during the study. 
Subjects must use a reliable method of contraception10, as follows.   
Men 
Male subjects must not plan to father a child, or donate sperm, from dosing until 3 
months after their (last) dose.   
Male subjects must not have sex without using a condom, from dosing until 3 months 
after their (last) dose, if their partner is a woman of childbearing potential.  They do 
not need to use any contraception if:  they’ve had a vasectomy, and surgical success 
has been confirmed by medical assessment; their partner has had a bilateral tubal 
ligation; or their partner is not of childbearing potential.  Partners who are not of 
childbearing potential are defined as:  men; post-menopausal women (no menstrual 
periods for at least 12 months); or women who have no uterus, ovaries or fallopian 
tubes.   
Women  
Women of childbearing potential must use a highly effective method of 
contraception with low-user dependency during the trial, and for up to one month 
after the final follow up visit.  They must have been using that method for at least 
28 days before the start of the trial.  Highly effective methods of contraception 
include:  
• Progestogen-only hormonal contraception implants associated with inhibition of 
ovulation 
• Intrauterine device (IUD) 


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• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion or ligation 
• Vasectomised partner (with surgical success confirmed by medical assessment) 
A woman is considered to be of non-childbearing potential if she meets one of the 
following criteria: 
• is post-menopausal (the last menstrual period was at least 12 months ago, and 
Follicle Stimulating Hormone (FSH) test at screening confirms post-menopausal 
status) 
• has no uterus, ovaries or fallopian tubes 
Women who are taking HRT must use contraception (as described above) during the 
trial unless prescribed following bilateral oophorectomy, hysterectomy or 
salpingectomy.   
Combined or progesterone-only hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal or injections) are not allowed.   
Subjects who practise true abstinence or who only have same-sex relationships need 
not use contraception, provided it is in line with their preferred and usual lifestyle 
(note:  periodic abstinence [eg calendar, ovulation, symptothermal, and 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception).  Should any such subject stop practising true abstinence, they must 
use contraception as described above. 
12 
Procedures and observations 
Only subjects who meet all the inclusion and no exclusion criteria will be eligible for 
enrolment into the trial (see section 9).  Each subject will be allocated a unique trial 
number (see section 10.5). 
Additional time points may be introduced, and changes to time points may be made, 
in accordance with section 12.2. 
The following assessments will be made at the timepoints given in in sections 12.1.1 
(Part A) and 12.1.2 (Part B). 
Safety and tolerability 
Laboratory assessments (haematology, biochemistry and urinalysis), physical 
examinations, 12-lead ECGs, vital signs (heart rate, blood pressure, respiratory rate, 
pulse oximetry and temperature), nasal examinations and spirometry will be done 
before and during dosing and frequently until the subject’s last visit in each study 
part.  Subjects will complete a tolerability questionnaire post-dose after each dose of 
Neumifil.  AEs will be recorded from screening until the subject’s last visit in each 
study part.   
The schedules of procedures are in sections 12.1.1 (Part A) and 12.1.2 (Part B).  
Laboratory safety variables to be assessed during the study are in Table 7. 


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Throughout the study, AEs and concomitant medication will be documented as they 
are reported by the subjects.  Subjects will be questioned about AEs when procedures 
are done, and when they return to the ward for outpatient visits (Part B only), and at 
follow-up.  
Plasma concentration of Neumifil 
Blood samples for assay of Neumifil will be taken before and up to 3 h after dosing 
on Day 1 (Part A) and Days 1 and 7 (Part B). 
Immunogenicity  
Blood samples for assay of Neumifil ADAs will be taken before dosing on Day 1 and 
on Day 22 (Part B only).  








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Abbreviations:  OP:  outpatient visit; ECG: electrocardiogram; FSH: follicle-stimulating hormone; PK: pharmacokinetics; ADA:  anti-drug antibodies; AEs:  
adverse events.   
Notes: 
1. 
Screening will be within 35 days before dosing  
2. 
Follow up will be 14 days (± 1 day) after the last dose. 
3. 
Full physical examinations will be done at screening and Day –1.  Brief (symptom-directed) physical examinations will be done at all other 
timepoints. Subjects may be referred for chest x-ray if the chest examination results are of clinical concern. 
4. 
Height measured at screening only. 
5. 
Vital signs consist of:  systolic and diastolic blood pressure, heart rate, temperature, pulse oximetry and respiratory rate.  They will be assessed 
at screening; on Day –1, and before and at 2, 4, 8, 12 and 24 h after dosing on Days 1 and 7; at the outpatient visit; and at follow-up.  Triplicate 
measurements (at least 2 min apart) will be made at screening and before dosing.  Single measurements will be made at all other time points.  
Measurements should be made with subjects in a supine position, after resting for 5 min. 
6. 
ECGs will be recorded at screening; before and at 2.5 h after dosing on Days 1 and 7; and at follow-up.  Triplicate recordings (to at least 2 min 
apart) will be made at screening; single recordings will be done at all other time points.  Recordings should be made with subjects in a supine 
position, after resting for 5 min. 
7. 
Laboratory safety tests consist of biochemistry, haematology and urinalysis in serum.  They will be done at screening; on Day –1; at 24 h after 
dosing on Day 1; on Day 8; at the outpatient visit; and at follow-up.  Subjects should fast for  8 h before laboratory safety tests at screening, 
admission (Day –1), and follow-up. 
8. 
Pregnancy tests in women of child-bearing potential only.   
9. 
FSH tests in post-menopausal women at screening only. 
10. FEV1 and FVC will be measured at screening; at 4, 8, 12 and 24 after dosing on Days 1 and 7; at the outpatient visit; and at follow-up. 
11. If a subject develops symptoms of COVID-19, ad hoc SARS-CoV-2 infection tests will be done. 
12. Self-assessment nasal tolerability questionnaires will be completed at 1 and 12 h post dose after each dose of Neumifil. 
13. Once-daily intranasal doses of Neumifil. 
14. Blood samples for assay of Neumifil will be taken: 
• 
before and at 1, 2, and 3 h after dosing on Days 1 and 7  
15. Blood samples for assay of Neumifil ADAs will be taken before dosing on Day 1, and at follow-up.   
16. Nasal wick samples will be taken before the evening meal on Day –1, or not less than 2 h after food at all timepoints. 
When more than one procedure is scheduled at a specific time point, procedures should be done in the following order:  ECG, vital signs, blood 
samples (at the scheduled time), then spirometry.  Blood sampling should be done on time.  Other procedures should be done as close as possible to 
the scheduled time point. 


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12.2 
Sampling time points and additional tests 
With the sponsor’s approval, additional time points may be introduced, and changes 
to time points may be made, if we have reason to believe that the change might 
improve the quality of the data (for example, if we believe that an important effect of 
the IMP is occurring at a time when no measurements are scheduled), or if extra 
procedures are needed in the interest of subject safety.  However, the total volume of 
blood taken in the trial will not exceed the value given in section 12.5.  Any 
additional urine collections may include continuous, total collections, if necessary.  
An additional 48 hours’ residence in the ward, and additional outpatient visits, will 
be permitted, in the event of a technical failure, and/or if extra observations or 
samples of blood or urine are needed.   
Extra procedures and changes to time points which have a significant impact on the 
scientific value and/or safety of the trial participants will be implemented only after 
approval of a substantial amendment from the Regulatory Authority (MHRA), unless 
the changes constitute an urgent safety measure. 
The following will not be regarded as protocol deviations.  
Table 5 
Acceptable deviation times (Part A) 
Procedure 
Timepoint 
Acceptable deviation  
PK blood 
sampling 
Predose on Day 1 
Up to 30 min before dosing 
1 h to 3 h post dose 
± 10 min of the scheduled time 
All other 
procedures* 
Pre-dose on Day 1 
Up to 90 min before dosing* 
Up to and including 4 h post dose 
± 10 min of the scheduled time 
After 4 h to 24 h post dose 
± 15 min of the scheduled time 
Outpatient visits 
± 1 day 
* samples for urinalysis may be collected anytime from when the subject awakes until the 
scheduled time. 
Table 6 
Acceptable deviation times (Part B) 
Procedure 
Study day 
Timepoint 
Acceptable deviation  
PK blood 
sampling 
Days 1 and 7 
Predose 
Up to 30 min before dosing 
1 h to 3 h post dose 
± 15 min of the scheduled time 
All other 
procedures* 
Days 1 and 7 
Pre-dose 
Up to 90 min before dosing* 
Up to and including 
4 h post dose 
± 10 min of the scheduled time 
After 4 h to 24 h 
post dose 
± 15 min of the scheduled time 
Days 2–6 
Predose 
Before dosing 
Day 8 
> 24 h post dose 
±1 h of the scheduled time 
Day 9 
onward 
Outpatient visits 
± 1 day 
* samples for urinalysis may be collected anytime from when the subject awakes until 
the scheduled time. 


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12.3 
Follow-up 
Subjects will return to the ward about 7 (Part A) or 14 (Part B) days after their (final) 
dose of trial medication for a follow-up visit.  Withdrawn subjects who consent to a 
follow-up visit will undergo the same procedures (see section 9.4). 
The follow-up period may be extended if: 
1. a subject has an unresolved AE at the follow-up visit, which, in the opinion of the 
investigator, merits further follow-up; or 
2. new information becomes available that supports an extended follow-up period. 
The investigator will decide on the nature of the follow-up.  For example, subjects 
may have a telephone follow-up at which they are asked about AEs, or subjects may 
be asked to attend extra outpatient visits for additional monitoring of effects of IMP, 
and for extra safety tests.  The extra safety tests might include tests that are not 
described in this protocol.  The investigator reserves the right, during or after the 
study, to repeat safety tests or to do any extra safety tests that are in the best interest 
of the subjects.  Those extra tests may or may not be described in this protocol. 
12.4 
Methods 
Blood collection 
Blood will be taken by venepuncture or via a cannula.  Cannulae will be inserted 
under local anaesthesia with lidocaine 0.5%, for withdrawal of venous blood.   
After each blood sample, the cannula will be flushed with 3–5 mL normal saline, to 
keep it patent.  In order to minimise dilution of each subsequent blood sample with 
normal saline, the following procedure will be used:  about 1 mL will be drawn via 
the cannula into the sampling syringe and discarded.  The definitive blood sample 
will then be taken. 
Blood volumes of specific types of samples may vary from those described below, 
but any change to the sample volumes will not cause the total volume of blood taken 
during the study to exceed that given in section 12.5. 
Samples for laboratory safety tests 
Blood will be taken for: 
• haematology (2 mL in EDTA) 
• biochemistry (3.5 mL in tubes with a gelatin plug) 
• serology (3.5 mL in tubes with a gelatin plug) 
• serum pregnancy/FSH (3.5 mL in tubes with a gelatin plug; serology sample used 
at screening)  
Blood samples will be collected into 13 × 75 mm tubes.  Urine will be collected in 
Universal containers.  Samples will then be transferred to the laboratory.  For 


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logistical reasons, blood and/or urine samples may be collected in tubes other than 
those stated below.   
Processing and analysis of samples for laboratory safety tests 
Processing of samples will be done by the HMR Analytical Laboratory in accordance 
with the laboratory’s SOPs. 
The HMR Analytical Laboratory will do safety tests on blood and urine samples 
using instruments interfaced to a validated laboratory information management 
system (LIMS).  Data from analysers that are not interfaced will be entered manually 
into the LIMS.   
Table 7 
Laboratory safety tests 
Haematology: 
• haemoglobin (Hb) 
• red blood cells (RBC) 
• mean corpuscular volume (MCV) 
• mean corpuscular haemoglobin (MCH)  
• mean corpuscular haemoglobin 
concentration (MCHC) 
• haematocrit 
• white blood cells (WBC) and differential 
(neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
• platelets 
Biochemistry: 
• urea 
• creatinine 
• uric acid 
• total bilirubin 
• total protein 
• albumin 
• globulin 
• alkaline phosphatase (AP) 
• aspartate aminotransferase (AST) 
• alanine aminotransferase (ALT) 
• gamma-glutamyl transpeptidase 
(GGT) 
• glucose* 
• phosphate 
• cholesterol 
• triglycerides 
• potassium 
• sodium 
• calcium 
• chloride 
• C-reactive protein (CRP) 
* fasting at screening, on Day –1 and at 
Follow-up 
# performed if result for hepatitis C 
antibody is positive 
 
Urinalysis: 
• dipstick:  protein, blood, ketones, glucose, 
bilirubin, urobilinogen, leukocyte esterase, 
specific gravity, nitrites, pH 
• microscopy:  only if dipstick test for 
protein, blood, leukocyte esterase or nitrites 
is abnormal 
Serology: 
• hepatitis B (hepatitis B surface antigen)  
• hepatitis C antibody 
• hepatitis C RNA# 
• HIV screen (HIV 1 and 2) 
 
Pregnancy tests 
Serum pregnancy tests will be done using an immunoenzymatic method.   


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FSH tests 
Serum FSH tests will be done using a chemiluminescent immunoassay method. 
Drugs of abuse, alcohol and cotinine tests 
Urine will be tested for drugs of abuse, alcohol and cotinine according to the 
laboratory’s SOP.  Tests will include:  amphetamines, cocaine, opiates, cannabis, 
barbiturates, benzodiazepines, alcohol and cotinine. 
Processing of blood samples for analysis of plasma concentration of Neumifil 
5 mL blood will be collected in will be taken into K2EDTA tubes, and immediately 
placed on ice.  Samples will be centrifuged at 2000 G for 10 min at 4 ºC and divided 
into 2 aliquots of approximately equal volume (minimum of 200 µL in the primary 
aliquot) in 1.8 mL screw-capped polypropylene cryotubes.  Plasma samples will be 
frozen at about _70 °C or below within 1 h after collection, and stored until dispatch 
to Alderley Analytical Ltd for analysis. 
Processing of blood samples for anti-drug antibody analysis 
5 mL blood will be collected in BD Vacutainer® rapid serum 5 mL tubes, and left at 
room temperature for 5 mins to clot.  Samples will be centrifuged at 2000 G for 
10 min at 4 ºC and stored on ice until they are divided into aliquots.  Each sample 
will be divided into 2 aliquots of approximately equal volume (minimum of 1.5 mL 
in the primary aliquot) in 2 mL screw-capped polypropylene cryotubes.  Serum 
samples will be frozen at about _70 °C or below within 30 min after collection and 
stored until dispatch to Kymos for analysis.  
Physical examination 
Physical examination will be done by a physician.  Brief physical examinations will 
be done at the timepoints in the schedule of procedures (section 12.1) if clinically 
indicated.  The following systems/sites will be examined during brief physical 
examinations:  cardiovascular, respiratory, abdomen, nose examination (including 
rhinoscopy), and other.  Full physical examinations will be given at all other 
timepoints.  The following will be examined during full physical examinations:  
general appearance; head, ears, eyes, nose and throat; thyroid; lymph nodes; back 
and neck; heart; chest (including auscultation for crepitations and reduced air entry, 
and percussion for dullness); lungs; abdomen; skin; and extremities; and the 
following systems will be assessed:  musculoskeletal and neurological. 
If the chest examination result is of clinical concern, the subject may be referred to a 
clinic for investigative chest x-ray (Part B only). 
Height and weight 
Height and weight will be measured by trained staff at HMR. 


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Vital signs 
Blood pressure and heart rate will be measured using SpaceLabs oscillometric 
equipment.  Measurements will be made with subjects in a supine position; subjects 
will remain supine for at least 5 min before vital signs are measured.   
Tympanic temperature will be measured using digital thermometers. 
Respiratory rate will be measured by observation of the chest. 
Peripheral arterial oxygen saturation (SpO2%) will be assessed using pulse 
oximetry. 
Repeat vital signs measurements 
During the trial, if vital signs fall outside the ranges below, a physician will review 
and decide on an appropriate course of action. The procedure will only be repeated if 
instructed by a physician.  
Supine systolic blood pressure:  
90–140 mm Hg 
Supine diastolic blood pressure:  
40–90 mm Hg 
Supine heart rate:  
40–100 beats/min 
Temperature:  
35.5–37.8 °C  
Respiration rate:  
10–16 breaths/min 
If the result of the repeat measurement is still out of range, the investigator will 
decide on an appropriate course of action.   
Standard 12-lead ECGs 
12-lead ECGs will be recorded using Mortara ELI250c and ELI280 cardiographs.  
Each recording will be printed on a single A4 page at paper speed 25 mm/sec and 
calibrated to 10 mm/mV.  Recordings will be made with subjects in a supine 
position; subjects will remain supine for at least 10 min before the ECG is recorded.  
PR, RR, QRS and QT intervals will be captured on source documents.  QT interval 
will be corrected using Fridericia’s formula (QTcF).   
During the trial, if ECG values fall outside the ranges below, a physician will review 
and decide on an appropriate course of action.  The procedure will only be repeated 
if instructed by a physician. 
Ventricular rate: 
35–100 beats/min 
PR interval: 
110–220 msec 
QRS: 
≤ 120 msec 
QTcF (men): 
QTcF (women): 
≤ 450 msec 
≤ 470 msec 
If the result of the repeat measurement is still out of range, the investigator will 
decide on an appropriate course of action.   
Forced expiratory volume test 
FEV1 and FVC will be measured using a CareFusion Micro lab MK8 spirometer. 
Nasal examination 
At screening, subjects will be asked whether any part of the nose is tender, sore, or 
irritating, and whether their sense of smell is normal for them.  An external 


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examination of the nose will be done, and significant abnormalities or erythema will 
be recorded.  A nasal speculum will be used to inspect the nose and assess whether 
nasal polyps, inflammation or erythema are present. 
At specified times during the study, subjects will be asked whether any part of the 
nose is tender, sore, or irritating, and whether their sense of smell has changed since 
the start of the study.  An external examination of the nose will be done, and 
abnormalities, inflammation or erythema will be recorded, as well as any changes 
from baseline (screening), or the previous examination.  A nasal speculum will be 
used to inspect the nose and assess whether abnormalities, inflammation, or erythema 
are present, as well as any changes from baseline (screening) or the previous 
examination. 
Subject self-reported dosing experience 
Subjects will complete a self-reported dosing and post-dosing questionnaire.  
Subjects are asked to assess whether they experienced any of the following using a 
numerical rating scale from 0 to 10: 
• Pain or stinging in the nose 
• Burning sensation or sensation of heat/hotness in the nose 
• Bleeding from the nose 
• Sensation of needing to blow their nose 
• General irritation in the nose 
• Sneezing 
• Marked change in the sense of taste or smell 
• Unpleasant taste 
To reduce variability, subjects will be able to see their previous responses.  A copy of 
the questionnaire can be found in Appendix 1 (section 22). 
Nasal wick sampling 
Nasal wicks will be used to collect samples of nasal secretions for measurement of 
cytokines and chemokines (including but not limited to IL-1, IL-3, IL-10, TNF-α, 
MCP-1 and IP-10), using a multiplex assay. 
12.5 
Total volume of blood removed 
The total volume of blood taken from each volunteer in the trial will be about 52 mL 
in Part A, and 93.5 mL in Part B, as stated in Table 8 (Part A) and Table 9 (Part B), 
respectively.  Additional blood samples for assay of Neumifil plasma concentration, 
ADAs, or for laboratory safety tests may be taken as described in section 12.2.  No 
more than an extra 80 mL of blood will be taken from any subject.   


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Table 8 
Planned blood volume (Part A) 
Test 
Planned number of 
tests 
Volume  
(mL) 
Total planned 
blood volume 
(mL) 
Haematology 
6 
2 
12 
Biochemistry 
6 
3.5 
21 
Serology (and FSH) 
1 
3.5 
3.5 
Pregnancy* 
2 
3.5 
3.5 
Plasma Neumifil 
4 
2 
8 
Discard (when using 
a cannula) 
4 
1 
4 
 
 
Total 
52 mL 
*included in serology sample at screening 
Table 9 
Planned blood volume (Part B) 
Test 
Planned number of 
tests 
Volume  
(mL) 
Total planned 
blood volume 
(mL) 
Haematology 
6 
2 
12 
Biochemistry 
6 
3.5 
21 
Serology (and FSH) 
1 
3.5 
3.5 
Pregnancy* 
2 
3.5 
7 
Plasma Neumifil 
8 
5 
40 
ADAs 
2 
5 
10 
Discard (when 
using a cannula) 
8 
1 
8 
 
 
Total 
93.5 mL 
*included in serology sample at screening 
13 
Trial materials 
13.1 
Identity of test product 
 
 
  


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The sponsor will provide to HMR a certificate of analysis for the test product, and, if 
applicable, any other documents and data required by HMR’s Qualified Person (QP) 
to release batches of IMP.   
13.2 
Packaging and labelling 
The trial medication will be prepared, packaged, and labelled by the HMR Pharmacy, 
in accordance with The Rules Governing Medicinal Products in the European Union, 
Volume 4:  Good Manufacturing Practice (GMP), and with HMR’s Manufacturing 
Authorisation for IMPs (MIA[IMP]).  The IMP labels will include all the information 
required by Annex 13 to GMP11.   
13.3 
Storage and accountability of IMP 
The IMP will be stored and accounted for according to GMP and HMR SOPs. 
At the end of the trial, all unused IMP supplies will be returned to the sponsor or 
destroyed in accordance with the sponsor’s instructions.  Further details will be 
provided in the IMP handling manual. 
14 
Adverse events 
14.1 
Definitions of adverse events 
Adverse event (AE) 
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 
that treatment.   
Adverse drug reaction (AR) 
All untoward and unintended responses to an IMP related to any dose administered. 
Note that, according to the ICH Guideline for Good Clinical Practice (ICH GCP), a 
causal relationship between the medicinal product and the AE is at least a reasonable 
possibility, ie a relationship cannot be ruled out. 
Unexpected adverse drug reaction 
An AR, the nature or severity of which is not consistent with the applicable product 
information (eg Investigator’s Brochure [IB] for an unauthorised investigational 
product, or summary of product characteristics for an authorised product). 
Serious adverse event (SAE) or serious adverse drug reaction (SAR) 
An AE or AR that: 
• is fatal; 
• is life-threatening;  


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• requires or prolongs inpatient treatment;  
• results in persistent or significant disability or incapacity; or 
• is a congenital anomaly or birth defect. 
Note: 
the term ‘life-threatening’ in the definition of ‘serious’ refers to an event or 
reaction in which the patient was at risk of death at the time of the event; it does 
not refer to an event or reaction which hypothetically might have caused death 
had it been more severe; and  
in accordance with the ICH Guideline on Clinical Safety Data Management:  
Definitions and Standards of Expedited Reporting, events or reactions that are 
not immediately life-threatening or may not result in death or hospitalisation but 
might jeopardise the subject or require intervention to prevent one of the other 
outcomes listed above, should usually be considered serious. 
Significant AE or AR 
An AE or AR which is not serious but is otherwise significant.  The following should 
normally be considered significant:  
• a marked haematological or other laboratory abnormality;  
• an AE or AR that leads to an intervention, including withdrawal of drug 
treatment, dose reduction or significant additional concomitant therapy; or 
• any AE or AR that the investigator considers to be significant. 
14.2 
Procedures for recording adverse events 
Subjects will be carefully monitored for AEs. The investigator or delegate will 
question the subjects about AEs using a non-leading question, such as ‘How are you 
feeling?’.  The investigator will also record AEs reported spontaneously by the 
subjects.  Clinically significant changes in the findings of physical examination, and 
clinically significant abnormalities in the results of objective tests (eg laboratory 
variables, ECG) may also be recorded as AEs.  Nasal tolerability questionnaire 
scores > 0 will be recorded as AEs. 
 The investigator will use the following criteria when deciding whether to report an 
abnormal result as an AE. 
1. 
The test result is associated with accompanying symptoms. 
2. 
Results of additional diagnostic tests cause concern or necessitate medical 
intervention. 
3. 
As a consequence of the test result, the subject is withdrawn, or the subject is 
given concomitant treatment. 
4. 
The investigator considers the result to constitute an AE. 


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If any of the above criteria are met, the investigator will report the result as an AE. 
A record will be kept in the source documents of all AEs as reported, whether 
believed to be related or unrelated to the treatment.  The record will include the 
following. 
• Clinical symptoms: a simple, brief description. 
• Date and time of onset and end of clinical symptoms. 
• Frequency:  constant or intermittent. 
• Severity.  The following categories will be used: 
Mild:  the AE does not interfere with the volunteer’s daily routine and does not 
require intervention; it causes slight discomfort. 
Moderate:  the AE interferes with some aspects of the volunteer’s routine, or 
requires intervention, but is not damaging to health; it causes moderate 
discomfort. 
Severe:  the AE results in alteration, discomfort or disability which is clearly 
damaging to health. 
• Relationship to treatment:  the assessment of relationship of AEs to the 
administration of IMP is a clinical decision based on all available information at 
the time of the completion of the case report form.  The following categories will 
be used. 
Related 
An event for which, after careful medical evaluation, a connection with trial 
medication cannot be ruled out with certainty. The event occurs after exposure to 
trial medication.  The event may occur at a reasonable time in relation to the time 
of administration of the trial medication but might also be attributable to a 
commonly occurring alternative cause.  Alternatively, the event may not occur at 
a reasonable time in relation to the time of administration of trial medication but 
may not be attributable to an alternative cause. 
Not related 
An event which occurs before exposure to the trial medication, or which does not 
occur at a reasonable time in relation to the time of administration of trial 
medication and can be attributed to a commonly occurring alternative cause.  
Alternatively, the event is unrelated to the trial (eg road traffic accident), unless it 
can be demonstrated that the treatment could have caused the event. 
• Action taken:  none, drug treatment, subject withdrawn, other (specified). 
• Outcome:  recovered/resolved, recovering/resolving (or not recovered/not 
resolved), or unknown. 


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14.3 
Procedures for dealing with serious adverse events 
In the event of any SAE which, in the investigator’s opinion, justifies termination or 
modification of the trial (see section 8.4), dosing will be stopped and the sponsor’s 
responsible physician will be informed immediately (within 24 h of the investigator 
becoming aware of the event) by telephone or email, as follows.   
Sponsor's 
responsible 
physician: 
 
 
Tel: 
 
Email: 
 
All SAEs occurring after the signing of the ICF until the follow up visit, regardless 
of study drug relationship, must be reported to the sponsor’s pharmacovigilance 
provider, with as much information as possible, within 24 h of the investigator 
becoming aware of the event.  The investigator will complete a serious adverse event 
form and provide it to the sponsor’s pharmacovigilance (PV) provider immediately 
(and within 24 hours of becoming aware of the event), via the following contact 
details. 
Diamond PV Services Limited 
Email (primary): 
PVServices@diamondpharmaservices.com 
Fax (back-up): 
+44 (0) 1279 418 964 
Tel (back-up): 
 +44 (0) 1279 406 759 
The sponsor will also be notified by email 
 
 
The investigator will notify the REC of SAEs that occur during this trial, if 
applicable, in accordance with the SOPs issued by the Research Ethics Service 
(RES). 
The sponsor is responsible for determining the expectedness of the event, using the 
reference safety information in the IB.  The sponsor will notify the MHRA of all 
suspected unexpected serious adverse reactions (SUSARs) and will be responsible 
for ensuring that the REC is notified of SUSARs, if applicable.  SUSARs that are 
fatal or life-threatening must be notified to the MHRA and REC within 7 days after 
the sponsor has learned of them.  Other SUSARs must be reported to the REC and 
MHRA within 15 days after the sponsor has learned of them. 
14.4 
Procedures for handling withdrawals due to adverse events 
The investigator will assess the reason for withdrawal as far as possible and will fully 
record the circumstances and medical details.  Provided that subjects give written 


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informed consent, they will undergo the standard medical examination and 
laboratory tests at withdrawal from the trial which they would have undergone had 
they completed it (see also section 9.4). 
14.5 
Procedures for reporting pregnancies 
Subjects will be asked to follow the contraception guidance in section 11. 
If, during the study, the investigator becomes aware of a pregnancy in a subject or 
their partner, they will inform the sponsor’s pharmacovigilance provider immediately 
(within 24 h of the investigator becoming aware of the event), as follows. 
Diamond PV services Limited 
Email (primary): 
PVServices@diamondpharmaservices.com  
Fax (back-up): 
+44 (0) 1279 418 964 
Tel (back-up): 
Tel (back-up): +44 (0) 1279 406 759 
The investigator will follow-up the pregnancy according to HMR SOPs, provided the 
subject (or their partner) consents to that.  A pregnancy will not constitute an SAE 
unless it meets one of the criteria in section 14.1. 
15 
Data management and quality assurance 
CRF source documents will be securely stored within HMR.  Data collected in 
source documents (see section 18.2) will be transcribed into an electronic CRF 
(eCRF). 
The investigator is responsible for ensuring the accuracy and completeness of the 
data entered into the eCRF, and the timeliness of data entry.  Clinical data (including 
AEs, concomitant medication, etc) will be entered into a 21 CFR Part 11-compliant 
Medrio M-1 database.  The Medrio M-1 system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate.  Data reported in the eCRF, derived from 
source documents, should be consistent with the source documents or the 
discrepancies should be explained.  Where the data violate data validation checks, 
queries will be generated for resolution by clinical staff.  All edits made to the 
database upon resolution of queries will be recorded in an electronic audit trail. 
The database will be locked after the following have been completed:  all expected 
eCRF data have been entered and accounted for; all discrepancies have been 
resolved; data have been coded as appropriate; SAEs have been reconciled; all site 
audit findings impacting the database have been closed; and quality control (QC) 
inspection has been completed. 
Data in source documents will be checked by the HMR Quality Assurance (QA) 
Department.  In addition, the HMR QA Department will audit the trial report; that 


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audit will include checks to ensure that statistical output is correctly reproduced in 
the report.  If requested, the investigator will provide the sponsor, MHRA, and REC 
with direct access to the original source documents. 
16 
Statistical methods 
16.1 
Statistical methods 
16.1.1 Planned analyses 
Final statistical analysis will be done by HMR.  A statistical analysis plan (SAP) will 
be prepared by the HMR Statistics and Data Management Department after 
completion of the final protocol and before first database lock. 
All statistical analysis and reporting will be done using SAS 9.4. 
16.1.2 Statistical hypotheses 
The trial is an exploratory one, and there are no null hypotheses to be tested.   
16.1.3 Analysis populations 
The following populations will be identified: 
Safety population: 
All subjects who received at least 1 dose of study 
drug.   
PK concentration population: All subjects who received at least 1 dose of study drug 
and for whom a PK sample has been analysed.  
PK parameter population: 
All subjects in the PK concentration population for 
whom PK parameters can be derived.  
PD population: 
All subjects in the safety population for whom a PD 
measure is available. 
Immunogenicity population: 
All subjects who received at least 1 dose of study drug 
and for whom an ADA sample has been analysed 
(Part B only).   
The primary endpoints will be analysed using the safety population for each study 
part. 
In all populations, treatment will be assigned based upon the treatment subjects 
actually received, regardless of the treatment to which they were randomised. 


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16.1.4 General considerations for data analyses 
The minimum set of summary statistics for numeric variables will be:  n, mean, 
standard deviation (or standard error), median, minimum, and maximum.  95% 
confidence intervals will be presented where appropriate for data interpretation.  
Categorical data will be summarised in frequency tables with n and percentage.  
Summaries of a categorical variable will include all recorded values. 
The minimum and maximum values will be presented to the same number of decimal 
places as the raw data collected in the CRF (or to 3 significant figures for derived 
parameters).  The mean, median and percentiles (eg Q1, and Q3) will be presented to 
one additional decimal place.  The standard deviation and standard error will be 
presented to 2 additional decimal places.  
‘Baseline’ will be the latest value obtained before IMP administration (predose on 
Day 1, or Day –1 if not recorded at predose, or screening if not recorded at predose 
or on Day –1 [eg weight]).  Out-of-range laboratory tests may be repeated.  If a test is 
out of-range at baseline and repeated before dosing, the latest repeat value before 
dosing will be used as baseline.  However, if a test is out-of-range and repeated at 
any other time during the study, the out-of-range value (not the repeat value) will be 
included in statistical summaries. 
16.1.5 Study population analyses 
16.1.5.1 Disposition of subjects 
The disposition of all subjects in the safety population will be summarised including:  
number of subjects randomised; number completing the study, by treatment; and 
number discontinued from the study. 
All subjects who withdraw or are withdrawn from the study will be listed, by 
treatment, with the reason for withdrawal. 
16.1.5.2 Demographic and baseline characteristics 
Demographic and baseline characteristics (eg physical examination, vital signs and 
ECGs) will be summarised.  
Subjects who take concomitant medication will be listed.   
16.1.5.3 Treatment compliance 
Dates and times of dosing will be listed.  
16.1.6 Safety data analyses 
Summaries and listings of safety data will use the safety population.  


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16.1.6.1 Adverse events 
AEs will be coded using the version of the Medical Dictionary for Regulatory 
Activities (MedDRA) current at the time of database lock.   
All AEs will be listed. 
A treatment-emergent adverse event is an AE that emerges during treatment (having 
been absent before treatment) or that worsens after treatment12.  
The number of subjects with at least one TEAE will be tabulated by actual treatment 
and MedDRA system organ class and preferred term.   
For each of the following, the number of TEAEs and the number of subjects with 
TEAEs will be summarised by actual treatment as follows: 
• 
TEAEs, by system organ class and preferred term 
• 
TEAEs by system organ class, preferred term and severity 
• 
drug-related TEAEs, by system organ class and preferred term 
Subjects with more than one TEAE will be counted only once, at the maximum 
causality, for each system organ class and preferred term.  AEs with missing severity 
and/or causality will be treated as severe and possibly related, respectively. 
AEs leading to withdrawal, deaths and other SAEs will be listed separately (fatal 
events will be listed separately from non-fatal events).   
16.1.6.2 Clinical laboratory evaluations 
Data from haematology and clinical chemistry will be summarised by treatment.  
Any laboratory value outside the reference interval for that variable will be flagged 
with an ‘H’ if it is higher than the reference interval, and with an ‘L’ if it is lower.  
Additionally, if, during the course of the trial, a variable changes from baseline by 
more than a predetermined amount (as defined by the principal investigator), that 
value will receive a flag ‘I’ if increased, or ‘D’ if decreased.  Therefore, if a value 
both falls outside the reference interval and alters from the baseline value by more 
than the predetermined amount, it will attract a double flag and will be considered to 
be of potential clinical importance (PCI). 
All laboratory values of PCI will be listed.  In a separate listing, laboratory values of 
PCI will be listed with all related laboratory results (ie haematology or clinical 
chemistry).  Frequencies of laboratory values of PCI will be summarised. 
16.1.6.3 Other safety measures  
Vital signs at each planned assessment and change in vital signs from baseline at 
each planned post baseline assessment, will be summarised by actual treatment.  
Vital signs of PCI will be listed separately.  


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QT interval will be corrected using Fridericia's (QTcF) formulae.   
ECG variables will be summarised by treatment and time point.  Differences from 
baseline will be summarised by treatment and time point. 
QTcF > 450 msec and increases in QTcF from baseline (Day 1 predose) of 
> 30 msec will be considered to be of PCI.  The number of subjects with a QTcF 
value of PCI will be summarised by actual treatment and time point, giving the 
numbers of subjects with QTcF > 450 msec, > 480 msec and > 500 msec, and the 
numbers of subjects with increases in QTcF from baseline of > 30 msec and 
> 60 msec13.  A supporting listing of all subjects with a QTcF value of PCI, and a 
separate listing of ECG findings classified as abnormal by the investigator, will also 
be provided. 
Abnormal physical examination findings, (including nasal examination findings) will 
be listed. 
16.1.6.4 Immunogenicity assessment (Part B only) 
Analyses of ADAs to Neumifil will be listed and summarised by treatment group and 
timepoint.  This analysis will be reported separately to the clinical study report. 
16.1.7 Plasma concentration data analyses 
 Neumifil plasma concentration data will be listed by treatment and time point. 
16.1.8 Pharmacodynamic data analyses (Part B only) 
Presence of cytokines and chemokines will be listed and summarised by treatment 
and timepoint. 
PD concentrations at each planned assessment and change in PD concentrations from 
baseline at each planned post baseline assessment, will be summarised by actual 
treatment. 
16.2 
Determination of sample size 
Since this is a pilot trial, no formal sample size determination is appropriate.  
17 
Ethical and regulatory requirements 
The trial proposal will be reviewed by a recognised REC, and by the MHRA.  The 
trial will not proceed unless the sponsor obtains from the MHRA a clinical trial 
authorisation (CTA), and the REC gives a favourable opinion of the trial.   
The trial will be done at HMR, in compliance with The Medicines for Human Use 
(Clinical Trials) Regulations 2004 and current amendments15, The Medicines for 
Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations 201916, The 


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Human Medicines (Amendment etc) (EU Exit) Regulations of 2019 and 202017,18, 
GMP11, the SOPs issued by RES for RECs in the UK19, and Good Clinical Practice, 
which has its origins in the Declaration of Helsinki.  
All subjects must give written consent to participate in this trial.  Consent for 
screening evaluations may be obtained using the information and consent form for 
the HMR healthy volunteer panel, which has been approved by the Health Research 
Authority’s Generic Document Review Committee.  The trial specific information 
and consent form will be signed by the subject either before any screening evaluation 
or after the investigator confirms the eligibility of the subject for the trial and before 
the subject is randomised to receive the first administration of IMP.  Before giving 
consent, subjects must read the information sheet about the trial.  They must also 
read the consent form.  They will then discuss the trial with the investigator or his 
deputy and be given the opportunity to ask questions.  The trial-specific information 
sheet and the consent form must be approved by the REC. 
Each subject is free to withdraw from the trial at any time, without giving a reason.  
If a subject withdraws, the investigator will ask the subject to consent to a follow-up 
examination.  For withdrawn subjects, the investigator will use a special information 
and consent form which has been ethically approved.  If the subject consents to the 
follow-up examination but asks the investigator to destroy all identifiable samples 
taken from the subject and/or not enter into the eCRF results of the follow-up 
examination, the investigator will comply with the subject’s requests. 
The sponsor will ensure that the MHRA and the REC, are informed promptly of 
SUSARs (see section 14.3), and that any new reports of SUSARs from other ongoing 
trials of the IMPs under investigation in this trial are notified to the MHRA, and to 
the REC, if applicable.  The sponsor will provide the investigator, the REC and the 
MHRA with annual safety reports of the IMP under investigation, and listings of all 
suspected serious adverse reaction (SSAR) reports.  The sponsor will also inform the 
investigator promptly of any new safety or toxicology data that might affect the 
safety of the subjects in this study.   
The investigator will promptly inform the sponsor and, if applicable, the REC of any 
SAE that occurs during this trial (see section 14.3).  The investigator will provide the 
REC with annual progress reports of the trial, if the trial lasts longer than a year.   
The investigator will report to the REC any protocol deviation that is, in his opinion, 
of clinical significance.  The investigator will also inform the REC in the event of 
several deviations which, although of no clinical significance, cause inconvenience 
and/or discomfort to the volunteers.  The sponsor will notify the MHRA and REC of 
any serious breach of good clinical practice (for example, the investigator puts 
subjects’ safety at risk, falsifies data, or persistently fails to comply with this protocol 
or good clinical practice).  
Within 90 days after the end of the trial, the sponsor (or sponsor’s delegate) will 
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is terminated prematurely, those reports will be made within 15 days after the end of 
the trial. 
The sponsor will supply a summary of the clinical trial report to the MHRA and REC 
within 1 year after the end of the trial.  
Trial procedures at HMR will be subject to audits by the HMR QA Department, to 
ensure compliance with the protocol and applicable regulatory requirements. 
18 
Trial documentation 
18.1 
Protocol amendments 
After the protocol has been approved by the REC and the MHRA, no changes may 
be made without the agreement of both the investigator and the sponsor.   
The MHRA and REC do not need to approve any substantial change to the protocol 
that needs to be implemented urgently to avoid an immediate hazard to trial subjects.  
The sponsor will ensure that the MHRA and REC are informed of urgent 
amendments in accordance with The Medicines for Human Use (Clinical Trials) 
Regulations 2004 and current amendments15 and the SOPs issued by RES for NHS 
RECs15. 
All agreed protocol amendments will be recorded on a written agreement which will 
be signed and dated by the investigator and sponsor, and attached to the original 
protocol.  The REC and/or MHRA must approve substantial amendments before they 
are implemented.  
The standard text in our information and consent form template explains that the 
planned doses may change during the trial, and that we may give the subjects any 
dose that has been approved by the MHRA and REC for the trial.  However, if we 
want to reduce the planned dose, we consider it essential to fully inform the subject 
of our reasons, because a reduction in dose might be due to poor tolerability, and that 
might affect the subject’s decision to remain in the trial.  Wherever possible, we will 
obtain prior approval from the REC for the information and consent form that we 
give to subjects before we reduce the dose.  But, owing to the nature of trials on 
healthy volunteers, it is likely that we will sometimes have to implement an urgent 
amendment to lower the planned dose, to avoid immediate hazard to the subjects.  
We will fully inform the subjects of the reason for reducing the dose and will notify 
the REC and MHRA promptly of the urgent amendment, in accordance with 
statutory requirements. 
18.2 
Case report forms 
The eCRF will be designed and produced by HMR.   


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To preserve confidentiality, the CRF will not bear the subject’s name.  The subject 
number and/or HMR volunteer number will be used for identification.  Age (year of 
birth) will be collected on the eCRF, not full date of birth.  
Data entry into the eCRF is described in section 15. 
Source documents  
Before the start of the study, the sponsor and investigator will sign an agreement 
listing the source documents to be used in this trial.  
18.3 
Reporting of results 
HMR will prepare a draft report for discussion with the sponsor.  The report will 
contain results and discussion of the trial, to which will be attached tables, figures 
and listings in compliance with ICH E320. 
Completed eCRFs will be supplied separately to the sponsor by HMR. 
19 
Obligations of the sponsor and investigator 
19.1 
Monitoring, auditing and inspection 
The trial will be monitored by the sponsor.   
A sample of documents generated by HMR which form part of this trial, and the 
ensuing data, will be audited by the HMR Quality Assurance Department to assess 
compliance with the quality management system of HMR.  That system incorporates 
the requirements of The Medicines for Human Use (Clinical Trials) Regulations 
2004 (and current amendments)15, ICH GCP, GMP11, and the SOPs issued by RES 
for RECs in the UK19, and is based on ISO 9001.   
The sponsor may do a quality assurance audit, and regulatory authorities may inspect 
this study, at any time during or after the study.  The sponsor and investigator agree 
to allow auditors and inspectors direct access to all relevant documents, and to 
allocate time to discuss findings with the auditors or inspectors. 
19.2 
Compensation of volunteers 
The sponsor agrees to abide by the Association of the British Pharmaceutical 
Industry (ABPI) Guidelines for medical experiments in non-patient human 
volunteers (2018 edition)21, and undertakes to compensate the subjects for injuries 
which are considered, on the balance of probabilities, to have arisen as a result of 
their participation in the trial. 


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19.3 
Confidentiality 
All personal details of the participating subjects and the results of the trial will be 
kept strictly confidential.  Each subject’s GP (or equivalent physician) will be 
informed of the nature and timing of the trial. 
All unpublished documents including the protocol, the CRF, and the IB are 
confidential.  Those documents cannot be disclosed to a third party without the 
written consent of the sponsor.  However, submission of those documents to a REC 
is expressly permitted. 
The investigator agrees that the sponsor maintains the right to use the results of this 
trial, in their original form and/or in a global report, for submission to governmental 
and regulatory authorities of any country. 
19.4 
Publication 
If the data merit, the investigator and the sponsor will discuss the preparation of a 
manuscript for publication in a peer-reviewed professional journal or an abstract for 
presentation, oral or written, to a learned society or symposium.  Either party may 
undertake the task, but both must agree to the strategy before the work is started.  
Each party will allow the other 30 days to comment before any results are submitted 
for publication or presentation.  Authorship should reflect work done by the 
investigators and personnel of the sponsor, in accordance with generally recognised 
principles of scientific collaboration.  
19.5 
Archiving 
The sponsor and HMR will keep in a trial master file all the essential documents 
required by GCP.  HMR will ensure that the investigator’s master file, and all data 
generated during the trial, will be archived in a secure place for 15 years.  Documents 
will be stored such that they are readily available for inspection at the request of the 
sponsor or a regulatory authority.  Any transfer of ownership of the investigator’s 
data or documents will be documented, and the sponsor will be informed.   
20 
Premature termination of the trial 
The sponsor and investigator reserve the right to terminate this trial should severe 
AEs, SAEs or any other safety issue occur during the trial.  If the trial is terminated 
prematurely, and the sponsor or investigator, as appropriate, will provide a written 
statement of the reasons for termination.  The sponsor will ensure that the MHRA 
and REC are notified, as described in section 18. 


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21 
References 
1. Jang, HJ and Seong, BL (2019).  The Quest for a Truly Universal Influenza 
Vaccine.  Front Cell Infect Microbiol.  10; 9:  344 
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and the elderly.  Curr Opin Immunol.  Aug; 29:  38–42. 
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Q; Chen, Y; Shen, X R; Wang, X; Zheng, X S; Zhao, K; Chen, Q J; Deng, F; 
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pneumonia outbreak associated with a new coronavirus of probable bat origin. 
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5. Shajahan, A. Supekar, N. T. Gleinich, A. S. and Azadi, P. (2020). Deducing the 
N- and O- glycosylation profile of the spike protein of novel coronavirus 
SARS-CoV-2.  Anal. Glycobiol. 30, 12: 981–988 
6. Casalino, L. Gaieb, Z; Goldsmith, J. A. Hjorth, C. K; Dommer, A. C; Harbison, 
A. M; Fogarty, C A; Barros, E. P; Taylor, B. C; McLellan, J. S; Fadda, E and 
Amaro, R. E. (2020).  Beyond Shielding: The Roles of Glycans in the SARS-
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Taubera, S; Taylora, M. A; Aliasa, N; Hagana, R; Nashc, A. A; Websterb, R. G 
and Taylor, G. L. (2014).  Prevention of influenza by targeting host receptors 
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10. Clinical Trials Facilitation and Coordination Group. Recommendations related 
to contraception and pregnancy testing in clinical trials, dated 
21 September 2020. 


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11. The Rules Governing Medicinal Products in the European Union, Volume 4 – 
Good Manufacturing Practice, incorporating Directive 2003/94/EC. 
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Pharmaceutical Industry. 
 
 


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22 
Appendix 1:  Subject self-reported dosing and post-dosing 
experience 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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