Conditions: Complex Regional Pain Syndrome (CRPS)
Keywords: Neridronic Acid Neridronate CRPS reflex sympathetic dystrophy (RSD)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 182
Healthy volunteers: no

Brief summary:
The aim of this trial was to investigate the efficacy and safety of intravenous neridronic acid in subjects with Complex Regional Pain Syndrome (CRPS).

The trial consisted of an Enrollment Period lasting up to 60 days, Treatment Period A consisting of 4 infusions (neridronic acid or placebo) over 10 days, and a Follow-up Period 1 until Week 26.

At Week 26, participants not meeting the pre-specified criteria to continue into Treatment Period B continued in Follow-up Period 2 until Week 52. Participants meeting the pre-specified criteria entered the open-label Treatment Period B with 4 additional infusions (neridronic acid) over 10 days and follow-up visits until Week 52.

Detailed description:

Arms:
arm 1: Neridronic acid 100 mg - 4 intravenous (i.v.) infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The investigational medicinal product (IMP) was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration.

The maximum neridronic acid dose was 800 mg: 400 mg in Treatment Period A and 400 mg in Treatment Period B. arm 2: Matching placebo - 4 intravenous infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The IMP was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration.

Interventions: intervention 1: Neridronic acid 100 mg intervention 2: Placebo
Intervention descriptions: intervention 1: 100 mg neridronic acid supplied in glass vials in 8 mL of excipients. intervention 2: Glass vials with matching placebo.

Protocol document:
SAP_002.pdf: 
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
 
 
1.0
1342858
kf7013-02 SAP
Biostatistics Approval
06-Jun-2018 12:57 GMT+02
Clinical Approval
06-Jun-2018 13:25 GMT+02
Biostatistics Approval
07-Jun-2018 09:13 GMT+02
Safety Approval
10-Jun-2018 22:08 GMT+02
NCT03530345


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SDR-SAP-TRIAL-08
CONFIDENTIAL
No part of this document may be passed on, reproduced or published without written 
permission of Grünenthal
STATISTICAL ANALYSIS PLAN
Trial code:
KF7013-02
Title of trial:
Randomized, double-blind, placebo-controlled trial investigating 
the efficacy and safety of intravenous neridronic acid in subjects 
with complex regional pain syndrome (CRPS)
EudraCT number:
2016-003833-91
Universal Trial Number:
U1111-1187-8036
Development phase:
Phase III
Final Version
Date
DMS version number
05 Jun 2018
1.0
This document was approved according to the Grünenthal standard operating procedures.
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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS
2
1.1
LIST OF TABLES
5
1.2
LIST OF FIGURES
5
2
ABBREVIATIONS
6
3
INTRODUCTION
7
4
TRIAL OBJECTIVES
7
5
TRIAL DESIGN
10
5.1
Overall trial design and plan
10
5.2
Sample size
11
5.3
Randomization
11
6
OVERVIEW OF PLANNED ANALYSES
12
6.1
Final analysis
12
6.2
Interim analyses
12
7
DOCUMENT AND CHANGE HISTORY
12
7.1
Changes in analysis compared to the trial protocol
12
7.2
SAP amendment rationale
13
8
ANALYSIS CONVENTIONS
14
8.1
General principles
14
8.2
Definitions
15
8.2.1
Definition of subgroups
15
8.2.2
Further definitions
16
9
SUBJECT POPULATIONS
17
9.1
Enrolled Set
17
9.2
Allocated Set
17
9.3
Safety Set
17
9.4
Full Analysis Set
17
9.5
Pharmacokinetic Set
17
9.6
Pharmacodynamic Set
18
10
DISPOSITION
18
10.1
Subject disposition
18
10.2
Subject discontinuations
19
10.3
Protocol deviations
19
11
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
19
11.1
Subject demographics
20
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11.2
Other baseline characteristics
20
11.3
Subject medical history
20
11.3.1
Medical history
20
11.3.2
Dental history
20
11.3.3
Complex regional pain syndrome (CRPS) history
20
11.4
Prior and concomitant medication or therapy
21
12
EXPOSURE AND COMPLIANCE
21
12.1
Exposure
21
12.2
Compliance
22
13
EFFICACY ANALYSES
22
13.1
Primary endpoint
22
13.1.1
Average pain intensity (recorded in the eDiary)
22
13.1.2
Main analysis
23
13.1.3
Sensitivity analysis
23
13.2
Secondary endpoints
26
13.2.1
Average pain intensity (recorded on tablet computer)
26
13.2.2
Pain response to treatment (recorded on tablet computer)
26
13.2.3
Dynamic mechanical allodynia
27
13.2.4
Pressure pain threshold
27
13.2.5
Edema
28
13.2.6
Confirmatory testing strategy for secondary endpoints
28
13.3
Other efficacy data
29
13.3.1
Pain Intensity recording on the tablet computer.
29
13.3.2
Pain response based on pain intensity recordings on the tablet computer
29
13.3.3
Pain intensity recording in the electronic diary
30
13.3.4
Active range of motion (AROM)
30
13.3.5
CRPS Severity Score
31
13.3.6
Patient Global Impression of Change (PGIC)
32
13.3.7
Patient Global Impression of Severity (PGI-S).
32
13.3.8
EuroQoL-5 Dimension-5 level (EQ-5D-5L)
32
13.3.9
PROMIS-29 profile and PROMIS-EDDEP39
32
13.3.10
Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2) - 6 neuropathic 
items
33
13.3.11
Pain Catastrophizing Scale (PCS)
33
13.3.12
Pain Self Efficacy Questionnaire (PSEQ).
33
13.4
Health economic and work productivity data
34
13.4.1
Work Productivity and Activity Impairment Questionnaire: CRPS 
(WPAI: CRPS). (US sites only)
34
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13.4.2
Medical resources utilization. (US sites only)
34
14
ANALYSIS OF PHARMACOGENETIC DATA, OMICS DATA AND 
PHARMACOKINETIC AND PHARMACODYNAMIC 
PARAMETERS
34
14.1
Analysis of plasma concentration
35
14.2
Bone turnover markers and markers for disease severity or CRPS 
progression
35
15
SAFETY ANALYSES
36
15.1
Adverse events
36
15.1.1
Adverse event summaries
37
15.1.2
Incidence, incidence rates and number of events
38
15.2
Laboratory parameters, vital signs and ECG parameters
40
15.2.1
Laboratory parameters
40
15.2.2
Vital signs
43
15.2.3
Electrocardiogram
43
15.3
Physical examination
43
16
INTERIM ANALYSIS
43
16.1
Interim analysis of efficacy
43
17
REFERENCES
44
18
CHANGES TO THE SAP
45
18.1
Amendments
45
19
APPENDIX
45
19.1
Data derivation and analysis rules
45
19.1.1
General specifications
45
19.1.2
Disposition
48
19.1.3
Demographics and other baseline characteristics
48
19.1.4
Efficacy analysis
49
19.1.5
Analysis of pharmacokinetic and pharmacodynamic parameters
50
19.1.6
Safety analysis
50
19.2
List of statistical output documentation
55
19.3
Reference ranges and alert ranges
55
19.3.1
Reference ranges for vital signs
55
19.3.2
Sponsor-defined alert ranges for vital signs
56
19.3.3
Sponsor-defined alert ranges for ECG parameters
56
19.4
Laboratory parameters reported in US conventional units
56
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1.1
LIST OF TABLES
Table 1:
Use of analysis sets
15
Table 2:
Analysis of laboratory parameters
41
Table 3:
Presentation of descriptive statistics in clinical trials
46
Table 4: 
Reference ranges for vital signs parameters
56
Table 5: 
Sponsor-defined alert ranges for vital signs parameters
56
Table 6: 
Sponsor-defined alert ranges for ECG parameters
56
Table 7:
Laboratory parameters reported in US conventional units
57
1.2
LIST OF FIGURES
Figure 1:
Graphical overview about the imputation strategy
51
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2
ABBREVIATIONS
Abbreviation
Explanation
AE
Adverse event
ANCOVA
Analysis of covariance
ß-HCG
Beta-human chorionic gonadotropin
BAP
Bone alkaline phosphatase
BMI
Body mass index
CI
Confidence interval
CIR
(Crude) Incidence rate
CRPS
Complex regional pain syndrome
CV
Coefficient of variation
DMA
Dynamic mechanical allodynia
ECG
Electrocardiogram
EQ-5D-5L
EuroQoL-5 Dimension-5 level
FAS
Full Analysis Set
ICTR
Integrated clinical trial report
IMP
Investigational medicinal product
N
Number of subjects in population
NRS
Numerical rating scale
MAR
Missing at random
Max
Maximum
MNAR
Missing not at random
Min
Minimum
Q1
First quartile 
PCS
Pain Catastrophizing Scale
PDS
Pharmakodynamic Set
PGIC
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PKS
Pharmakokinetic Set
PMI
Placebo multiple imputation
PMM
Pattern mixture model
PSEQ
Pain Self Efficacy Questionnaire
PT
Preferred Term
Q3
Third quartile
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RR
Relative risk
SAE
Serious adverse event
SAF
Safety Set
SAP
Statistical analysis plan
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Abbreviation
Explanation
SAS
Statistical analysis software
SD
Standard deviation
TEAE
Treatment emergent adverse event
VAS
Visual analog scale
WPAI
Work Productivity and Activity Impairment Questionnaire
Système International d’Unités units are not included in this list.
3
INTRODUCTION
This statistical analysis plan (SAP) includes all definitions and analysis details for the analysis of 
the trial in accordance with the protocol dated 14 Mar 2018. The analysis will be performed by the 
sponsor in accordance with this SAP.
4
TRIAL OBJECTIVES
Objective
Endpoint/Outcome
Measure description and timeframe
Primary
Primary
Primary
To demonstrate the superior 
efficacy of a cumulative dose of 
400 mg intravenous neridronic 
acid versus placebo for the 
treatment of CRPS-related pain.
Change from baseline to 
Week 12 in the average pain 
intensity score (weekly average 
of pain values recorded daily in 
the electronic diary).
11-point numerical rating scale (NRS)—from
0 = “no pain” to 10 = “pain as bad as you can
imagine” —reported once daily (in the
evening, 24-hour recall) in an electronic diary.
The change from the baseline phase (Day -7 to
Day -1) to Week 12 will be analyzed.
Secondary
Secondary
Secondary
To assess the efficacy of a 
cumulative dose of 400 mg 
intravenous neridronic acid 
versus placebo for the treatment 
of CRPS-related pain.
Change from baseline to 
Week 26 in the average pain 
intensity recorded on the tablet 
computer.
11-point NRS—from 0 = “no pain” to
10 = “pain as bad as you can imagine”—
reported at the visits on a tablet computer (24-
hour recall). The change from baseline (Visit 2
[Day 1]) to Visit 11 (Week 26) will be
analyzed.
Pain response to treatment, 
defined as at least 30% decrease 
from baseline in the average 
pain intensity at Week 12, 
recorded on the tablet computer.
11-point NRS—from 0 = “no pain” to
10 = “pain as bad as you can imagine”—
reported at the visits on a tablet computer (24-
hour recall). The change from baseline (Visit 2
[Day 1]) to Visit 8 (Week 12) will be
analyzed.
Pain response to treatment, 
defined as at least 30% decrease 
from baseline in the average 
pain intensity at Week 26, 
recorded on the tablet computer.
11-point NRS—from 0 = “no pain” to
10 = “pain as bad as you can imagine”—
reported at the visits on a tablet computer (24-
hour recall). The change from baseline (Visit 2
[Day 1]) to Visit 11 (Week 26) will be
analyzed.
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Objective
Endpoint/Outcome
Measure description and timeframe
To assess the efficacy of a 
cumulative dose of 400 mg 
intravenous neridronic acid 
versus placebo on the dynamic 
mechanical allodynia (DMA).
Change from baseline to 
Week 12 in the pain intensity 
level of DMA.
Dynamic mechanical allodynia: a tactile 
stimulus is applied in a single sweeping 
motion (1 cm to 2 cm length) on the skin on 
the affected limb.
The subjects are asked to judge the stimulus 
intensity by means of an NRS (0 to 10). “0” in 
this case means “no pain”. Each “pricking”, 
“stinging” or “burning” sensation is defined as 
a painful sensation, which should always be 
evaluated by giving a value greater than “0”. 
“10” corresponds to the individual maximum 
pain imaginable.
The change from baseline (Visit 2 [Day 1]) to 
Visit 8 (Week 12) will be analyzed.
To assess the efficacy of a 
cumulative dose of 400 mg 
intravenous neridronic acid 
versus placebo on the pressure 
pain threshold (PPT).
Change from baseline to 
Week 12 in the PPT ratio for the 
thenar muscle/abductor hallucis 
muscle.
Pressure pain threshold: using a pressure 
algometer (contact area 1 cm2), the threshold 
for pressure-induced pain is measured on the 
thenar muscle/abductor hallucis muscle in 
3 series of slowly increasing stimulus 
intensities (at a rate of about 50 kPa/s). The 
threshold is then determined as the arithmetic 
mean of the 3 series (in kPa). 
The ratio of the thresholds of the affected limb 
versus the unaffected limb will be calculated.
The change from baseline (Visit 2 [Day 1]) to 
Visit 8 (Week 12) will be analyzed.
To assess the efficacy of a 
cumulative dose of 400 mg 
intravenous neridronic acid 
versus placebo on edema of the 
hand or foot.
Change from baseline to 
Week 12 in the ratio of the 
figure of eight measurements of 
the affected limb versus the 
unaffected limb.
In subjects with the CRPS sign of edema on 
the CRPS Severity Score at baseline, 
circumference of the hand or foot will be 
measured by the investigator with 
measurement tape using the figure-of-eight 
method at both the affected limb and the 
contralateral unaffected limb. Each 
measurement will be performed 3 times. The 
average of the 3 measurements will be used 
for further analysis.
The ratio of the averages of the affected limb 
versus the unaffected limb will be calculated.
The change from baseline (Visit 2 [Day 1]) to 
Visit 8 (Week 12) will be analyzed.
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Other data to be collected that are not directly attributed to or considered as an endpoint
General note: All efficacy and safety endpoints evaluated during Treatment Period B and Follow-up Period 2 will be 
analyzed descriptively separately for subjects who are treated in Treatment Period B and subjects who are not treated. 
For subjects treated in Treatment Period B, analyses will be performed for subjects initially treated with placebo and 
subjects initially treated with neridronic acid.
To assess the efficacy of neridronic acid in subjects with CRPS
•
Change from baseline to Week 52 in average pain intensity recorded on the tablet computer.
•
Change from Week 26 to Week 52 in average pain intensity recorded on the tablet computer.
•
Pain response to treatment, defined as at least 50% decrease from baseline in the average pain intensity at
Week 52, based on pain intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 50% decrease from Week 26 in the average pain intensity at
Week 52, based on pain intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 50% decrease from baseline in the average pain intensity at
Week 12, based on pain intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 50% decrease from baseline in the average pain intensity at
Week 26, based on pain intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 30% decrease from baseline in the average pain intensity at
Week 52, based on pain intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 30% decrease from Week 26 in the average pain intensity at
Week 52, based on pain intensity recordings on the tablet computer.
•
Change from baseline to Week 12 in pain intensity scores determined using worst and current pain ratings
recorded daily in the electronic diary.
•
Change from baseline to Week 26 in worst and current pain intensity ratings, recorded on the tablet
computer.
•
Change from baseline to Week 52 in worst and current pain intensity ratings, recorded on the tablet
computer.
•
Change from Week 26 to Week 52 in worst and current pain intensity ratings, recorded on the tablet
computer.
•
Change from baseline to Week 6, Week 26, Week 36, and Week 52 in the pain intensity level of DMA.
•
Change from baseline to Week 6, Week 26, Week 36, and Week 52 in PPT ratios.
•
Change from baseline to Week 6, Week 26, Week 36, and Week 52 in the ratio of the figure of eight
measurements of the affected limb versus the unaffected limb.
•
Change from baseline to Week 6, Week 12, Week 26, Week 36, and Week 52 in the active range of motion
(AROM) ratio (affected limb and unaffected limb) measured in the hand or foot, respectively.
•
Change from baseline to Week 12, Week 26, and Week 52 in the CRPS Severity Score.
•
Patient Global Impression of Change (PGIC) at Week 6, Week 12, Week 16, Week 22, Week 26, Week 28,
Week 36, and Week 52.
•
Change from baseline to Week 6, Week 12, Week 16, Week 22, Week 26, Week 28, Week 36, and
Week 52 in the Patient Global Impression of Severity (PGI-S).
•
Change from Week 26 to Week 52 in the PGI-S.
•
Change from baseline to Week 12 and Week 26 in the EuroQoL-5 Dimension-5 level (EQ-5D-5L) index
score and the health-related visual analog scale (VAS) score.
•
Change from baseline to Week 52 in the EQ-5D-5L index score and the health-related visual analog scale
score.
•
Change from Week 26 to Week 52 in the EQ-5D-5L index score and the health-related visual analog scale
score.
•
Change from baseline to Week 6, Week 12, Week 26, Week 28, Week 36, and Week 52 in the responses to
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questions on the following questionnaires (recorded on the tablet computer):
−
Patient-Reported Outcomes Measurement Information System (PROMIS®)-29 profile version 2.0 
(PROMIS-29 profile) (sub-scores: physical function, anxiety, depression, fatigue, sleep disturbance, 
social roles and activities, and pain interference). The change from baseline to Week 16 and Week 22 
will be assessed for question number 29, GLOBAL07 only.
−
Question EDDEP39 of the PROMIS Item Bank version 1.0 – Emotional Distress – Depression 
(PROMIS-EDDEP39).
−
The 6 neuropathic pain items of the Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2) (single 
items and the combined score).
−
Pain Catastrophizing Scale (PCS).
−
Pain Self Efficacy Questionnaire (PSEQ).
To describe the trial population and to evaluate subject eligibility
•
Demographic data, medical history, dental history, CRPS history, prior medication and therapies, beta-
human chorionic gonadotropin (ß-HCG) pregnancy test, and drugs of abuse test.
To assess the safety and tolerability of neridronic acid in subjects with CRPS
•
Adverse events, concomitant medications, physical examination findings, 12-lead electrocardiograms 
(ECGs), vital signs, body weight, and safety laboratory data.
To assess the pharmacodynamics of neridronic acid in subjects with CRPS
•
Concentrations of bone turnover markers in serum: (C-terminal telopeptide of type I collagen [CTX], bone 
alkaline phosphatase [BAP], and procollagen type I amino-terminal propeptide [PINP]).
To assess the pharmacokinetics of neridronic acid in subjects with CRPS
•
Concentrations of neridronic acid in plasma.
To assess health economics and work productivity (US sites only)
•
Work Productivity and Activity Impairment Questionnaire: CRPS (WPAI: CRPS).
•
Medical resources utilization.
To explore markers for disease severity or progression in CRPS
•
Concentrations of soluble interleukin-2 receptor (sIL-2R).
5
TRIAL DESIGN
5.1
Overall trial design and plan
Only a brief synopsis of the trial design is presented here; full details can be found in the trial 
protocol.
This is a multi-site, randomized, double-blind, placebo-controlled, 2-arm, Phase III trial of 
intravenous neridronic acid in subjects with complex regional pain syndrome (CRPS). The trial will 
consist of two treatment periods, Treatment Period A will be double-blind whereas Treatment 
Period B will be open-label. However, investigators and subjects will remain blinded to their initial 
treatment.
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There will be an Enrollment Period lasting up to 60 days, Treatment Period A consisting of 
4 infusions over 10 days, and Follow-up Period 1 from Visit 6 (Week 2) up until Visit 11 
(Week 26).
At Visit 11 (Week 26), subjects not meeting the pre-specified criteria to continue into Treatment 
Period B will continue in Follow-up Period 2 until Visit 17 (Week 52). Subjects meeting the pre-
specified criteria will enter the open-label Treatment Period B with 4 additional infusions over 
10 days and follow-up visits until Visit 17 (Week 52).
The IMP used in this trial are neridronic acid and matching placebo. 
Investigational medicinal product is supplied in glass vials, each containing 108 mg sodium 
neridronate hemi hydrate (equivalent to 100 mg neridronic acid) or matching placebo in a total 
volume of 8 ml. 
For subjects with no or mild renal impairment in Treatment Period A, the full contents of a single 
vial will be administered at Visit 2, Visit 3, Visit 4, and Visit 5, resulting in a total dose of 400 mg 
neridronic acid or matching placebo.
For subjects with no or mild renal impairment included in Treatment Period B, the full contents of a 
single vial will be administered at Visit 11, Visit 12, Visit 13, and Visit 14, resulting in a total dose 
of 400 mg neridronic acid.
Dose adaptations will be made in case of moderate renal impairment resulting in total doses of 
250 mg (CKD-EPI Stages 3b) or 300 mg neridronic acid (CKD-EPI Stages 3a).
5.2
Sample size
The sample size is based on a statistical test of the superiority of 400 mg neridronic acid versus 
placebo in the primary endpoint. The null hypothesis of no effect, H0: 0 ≤µ400 - µ0, is tested against 
the alternative hypothesis H1: µ400 - µ0<0. (Note: A pain reduction will be analyzed as a negative 
change from baseline. An effective treatment will lead to reduced pain and, hence, to a negative 
mean change from baseline, µ<0).
For a difference in the means of µ400 - µ0 = -1.0 points on the NRS, assuming a standard deviation 
of 2.0 points on the NRS and a 1-sided significance level of 2.5% (α = 0.025), 86 subjects per arm 
will be required to provide at least 90% power (1-β = 0.9) to reject the null hypothesis. To 
compensate for a slight decrease in power due to an optional futility interim analysis, a total of 
180 subjects (90 subjects per arm) are planned to be allocated to treatment.
5.3
Randomization 
On Day 1, subjects who comply with all inclusion criteria and do not meet any of the exclusion 
criteria will be randomly allocated to one of the two treatment groups in a 1:1 ratio stratified by 
geographic region. Treatment assignment will be performed centrally using an interactive response 
technology system prior to the first intravenous infusion of IMP.
The investigator (or delegate) must log into the system using their own user identification number 
and a password. The investigator (or delegate) will enter the subject’s number and other information 
required by the system to obtain a medication number. The medication number will then be used to 
select the correct package of IMP to give to the subject.
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The subject’s initial treatment will be blinded until the 26-week analysis. However, investigators 
and subjects will not be informed about the initial treatment allocation at any time before database 
lock of the full trial.
Randomization and blinding will be performed in accordance with the sponsor’s standard operating 
procedures (SOPs).
6
OVERVIEW OF PLANNED ANALYSES 
6.1
Final analysis
The primary analysis will be performed once all subjects have completed Visit 11 (Week 26), 
including database lock and unblinding. The results from this 26-week analysis will be reported in 
an interim integrated clinical trial report.
The final analysis of this trial, including Treatment Period B and Follow-up Period 2, will be 
performed after the last subject has completed the trial and the database has been locked.
6.2
Interim analyses
An interim analysis is planned after a combined total of approximately 80 subjects in the 2 Phase III 
trials, KF7013-02 and KF7013-04, have completed Week 12 of treatment and the data is available 
in the databases. The interim analysis is for futility only and will be non-binding. The futility 
criterion will be based on the unblinded comparison of the primary endpoint and will be calculated 
using identical methods as for the final analysis. If the observed difference in the means of µ400 -
µ0 is ≥ -0.3 points on the NRS, the null hypothesis will not be rejected and the recommendation 
will be to stop both trials. The interim analysis will be performed by an independent statistical 
analysis unit not otherwise involved in the conduct of the trial and the result will only state the 
recommendation to stop or continue the Phase III program. No unblinded information will be 
disseminated to the trial teams. Pending recruitment rates of both trials, it may be decided to forgo 
the interim analysis or conduct it a different point in time. As the interim analysis will be for futility 
only, no inflation of the type I error will occur.
The interim analysis will be further described in a separate SAP as it will be performed on the 
pooled data of 2 trials.
7
DOCUMENT AND CHANGE HISTORY
7.1
Changes in analysis compared to the trial protocol
Not applicable.
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Change from protocol 
Rationale for change
Section 1.2 Trial objectives, endpoints, and 
outcomes
Other data to be collected that are not 
directly attributed to or considered as an 
endpoint
•
Change from baseline to Week 6, Week 12, 
Week 26, Week 28, Week 36, and Week 52 in 
the responses to questions on the following 
questionnaires (recorded on the tablet 
computer):
−
Patient-Reported Outcomes Measurement 
Information System (PROMIS®)-29 
profile version 2.0 (PROMIS-29 profile) 
(sub-scores: physical function, anxiety, 
depression, fatigue, sleep disturbance, 
social roles and activities, and pain 
interference). The change from baseline to 
Week 16 and Week 22 will be assessed 
for question number 29, GLOBAL07 
only.
−
Question EDDEP39 of the PROMIS Item 
Bank version 1.0 – Emotional Distress –
Depression (PROMIS-EDDEP39) (not for 
Week 28).
−
The 6 neuropathic pain items of the Short-
Form McGill Pain Questionnaire 2 (SF-
MPQ-2) (single items and the combined 
score).
−
Pain Catastrophizing Scale (PCS) (not for 
Week 28).
−
Pain Self Efficacy Questionnaire (PSEQ) 
(not forWeek 28).
Schedule of events in protocol shows that these 
assessments are not done at Week 28.
Protocol Section 14.1.7.2 Analysis of the 
secondary endpoints
A logistic regression model will be fitted to the 
data, including the covariate baseline pain 
intensity score, and the factors geographic 
region, week, and treatment, and treatment-by-
week interaction as fixed effects. 
Change to logistic regression at respective 
weeks instead of longitudinal analysis to 
simplification of model fitting.
7.2
SAP amendment rationale
Not applicable.
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8
ANALYSIS CONVENTIONS
8.1
General principles
All presentations will be done by treatment group.
Presentation of treatment groups will differ for the Week 1 to Week 26 and Week 27 to Week 52. 
Treatment groups for Week 1 to Week 26 are Placebo and Neridronic acid 400mg. For presentation 
of Week 27 to Week 52 in the final report, subjects will be displayed based on their treatment in 
Treatment Period A Placebo and Neridronic acid 400 mg and whether they have been treated with 
neridronic acid in Treatment Period B. Hence, for the final report, 4 treatment arms will be 
presented: Placebo, Placebo + Treatment Period B, Neridronic acid 400 mg and Neridronic acid
400mg + Treatment Period B and, if applicable, information will be summarized in an overall 
group.
The results from the 26-week analysis will be reported in an interim integrated clinical trial report. 
The display of the efficacy results in this report will be limited to all data up until Visit 11/Week 26, 
safety data will be reported for all data until the respective cut-off date. For the final ICTR, TFLs 
and analysis will be extended and additionally all data assessed after Visit 11/Week 26 will be 
analyzed and displayed.
The data collected and derived in the trial will be presented in subject data listings sorted by site and 
treatment.
Data collected in this trial will be summarized according to their nature as follows if not specified 
otherwise:
•
Continuous variables: number of non-missing observations, arithmetic mean, standard 
deviation, minimum and maximum values, median and quartiles. If there are less than 
5 observations, descriptive statistics will be presented based on the rules specified in 
Section 19.1.1.2.
•
Categorical variables: absolute and relative frequencies. If not defined otherwise, the 
percentage denominator will be the number of subjects still in the trial (including missing 
values) at the respective time point in the analyzed population. The category missing will 
only be displayed if missing values occur.
•
Time-to-event variables: Kaplan-Meier estimates together with the 95% confidence 
intervals (CI) and the hazard rate will be provided with the respective number at risk and 
the number censored at the relevant time points. In addition, the median time-to-event and 
its 95% CI will be presented if applicable. For calculating the survival estimate CI bounds,
the log-log transformed estimate of CI bounds will be used. The time to event will be 
censored at the Visit 11 for the Week 26 report and End-of-Treatment Visit/End-of-Trial 
Visit for the final report if not otherwise specified. 
Medical terms (e.g., prior and concomitant diseases, adverse events) will be coded via Medical 
Dictionary for Regulatory Activities (MedDRA). For the analysis, the primary System Organ Class 
SOC will be used. Medications will be coded according to World Health Organization Drug 
Dictionary (WHO-DD). 
Table 1 shows the use of analysis sets in different analyses as defined in Section 9.
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Table 1:
Use of analysis sets
Enrolled Set
Allocated Set
SAF
FAS
PKS
PDS
Subject disposition
X
X
X
X
Discontinuations
X
X
X
X
Protocol deviations
X
Demographics
X
X
Other baseline characteristics
X
X
Subject medical and dental history
X
X
CRPS history
X
X
Prior and concomitant medication
X
X
Exposure
X
Compliance
X
Primary endpoint
X
Secondary endpoint
X
Adverse events
X
Laboratory values
X
Pharmacokinetic concentrations
X
Bone turnover markers
X
Soluble interleukin-2 receptor (sIL-2R)
X
Other safety parameter
X
FAS = Full Analysis Set, PDS = Pharmacodynamic Set, PKS = Pharmacokinetic Set, SAF = Safety Analysis Set
8.2
Definitions
8.2.1
Definition of subgroups
The following subgroups will be analyzed:
•
Gender (male, female).
•
Age (<65, >= 65).
•
Region (USA/Canada, Europe, and Other Regions [including Asia-Pacific and 
Australia/New Zealand]). 
Subgroup analyses will be limited to the primary endpoint and disposition and demographic 
information.
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8.2.2
Further definitions
Baseline 
Baseline is defined as the last observation (scheduled or unscheduled) 
before first IMP administration if not otherwise specified. In general, 
baseline is the value recorded at Visit 2.
More precisely, for post-baseline comparisons of all parameters except 
pain intensity in the eDiary, the assessment before first IMP 
administration at Visit 2 (Day 1) will serve as the baseline based on 
recorded date/times. In case the value planned on Day 1 is missing or 
in case there are multiple values before first IMP administration on 
Day 1, the last scheduled or unscheduled non-missing value before 
first IMP administration will be used.
For current, average, and worst pain, baseline pain intensity will be 
calculated as the average of the non-missing pain intensity ratings 
obtained over the 7-day baseline pain assessment phase prior to first 
IMP administration.
Investigational 
Medicinal Products 
(IMP) 
The IMPs used in this trial are neridronic acid and matching placebo.
On-treatment-period
For the purpose of this trial, the on-treatment period starts at the first 
IMP administration (included) and continues until the date (included) 
when the subject leaves the trial, i.e., at the Final Visit (Visit 17, week 
52 after Follow up period 2) for trial completers, and otherwise at the
End of Trial date for subjects not fully completing the trial. The on-
treatment period extends beyond the dosing period. This is because of 
the persistence in bone and potentially prolonged effect of neridronic 
acid.
Pooling of sites
Individual sites will be pooled by geographic region. Geographic 
regions are defined as USA/Canada, Europe, and Other Regions 
(including Asia-Pacific and Australia/New Zealand).
Pre-treatment-period
Before the first IMP administration (excluded).
Treatment Period A
completers
Treatment Period A completers are treated subjects who completed 
IMP administration in Treatment Period A according to the protocol, 
i.e., subjects who received the full dose of all 4 planned infusions.
Subjects are identified via the “Treatment Period A completer” page in 
the CRF based on the data point “Did the subject complete the 
treatment?”
Follow-up Period 1 
completers
Follow-up Period 1 completers are treated subjects who completed the 
Follow-up Period according to the protocol, i.e., subjects who have a 
Visit 11 not before Day 183. Subjects do not need to be Treatment A 
completers.
Treatment Period B 
Treatment Period B completers are treated subjects who completed 
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completers
IMP administration in Treatment Period B according to the protocol, 
i.e., subjects who received the full dose of all 4 planned infusions.
Subjects are identified via the “Treatment Period B completer” page in 
the CRF based on the data point “Did the subject complete the 
treatment?”
Follow-up Period 2 
completers
Follow-up Period 2 completers are treated subjects who completed the 
Follow-up Period 2 according to the protocol, i.e., subjects who have a 
Visit 17 not before Day 365. Subjects do not need to be Treatment 
Period A or Treatment Period B completers.
Trial completers
Trial completers are treated subjects who completed the trial according 
to the protocol. Subjects are identified via the End of Trial page in the 
CRF based on the data point “Trial fully completed?”
Subjects do not need to be Treatment Period A or Treatment Period B 
completers to fully complete the trial.
9
SUBJECT POPULATIONS
9.1
Enrolled Set
The Enrolled Set includes all subjects who signed the informed consent form.
9.2
Allocated Set
The Allocated Set includes all subjects who are allocated to treatment. Presentation of the Allocated 
Set will be conducted according to the allocated treatment.
9.3
Safety Set
The Safety Set (SAF) includes all subjects with at least 1 IMP administration including any partial 
infusion.
Analysis on the SAF will be conducted on the actual treatment received. Subjects that by accident 
switched treatment arm during the trial will be assigned to one treatment arm before unblinding.
9.4
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects allocated with at least 1 IMP administration, 
including any partial infusion. 
Analysis on the FAS will be conducted according to the allocated treatment.
9.5
Pharmacokinetic Set
The Pharmacokinetic Set (PKS) defines the subset of the subjects who have at least 1 evaluable 
pharmacokinetic concentration.
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9.6
Pharmacodynamic Set 
The Pharmacodynamic Set (PDS) defines all treated subjects with at least 1 non-missing value for 
at least 1 of the bone turnover markers.
10
DISPOSITION
10.1
Subject disposition
All presentations for subject disposition will be by treatment group and overall.
For describing the subject disposition, the following populations will be summarized, overall and 
for the following subgroups: gender, region and age group:
•
Display with percentage denominator being the number of enrolled subjects.
−
Subjects enrolled (only overall).
−
Subjects enrolled but not allocated and reason for non-allocation (only overall).
•
Displayed with percentage denominator being the number of allocated subjects. For the 
reasons for not being treated for subjects allocated but not treated, the percentage 
denominator is the number of allocated but not treated.
−
Subjects allocated (=Subjects allocated to Treatment Period A).
−
Subjects allocated but not treated and the reasons for not being treated.
−
SAF.
−
FAS.
−
Pharmacokinetic Set.
−
Pharmacodynamic Set.
−
Treatment Period A completers.
−
Follow-up Period 1 completers.
−
Treated in Treatment Period B.
−
Treatment Period B completers.
−
Follow-up Period 2 completers.
−
Trial completers treated only in Treatment period A.
−
Trial completers.
−
Subjects allocated and discontinued from IMP in Treatment Period A.
−
Subjects allocated and discontinued from the trial in Treatment Period A.
−
Subjects allocated and discontinued from the trial.
•
Displayed with percentage denominator being the number of subjects allocated in 
Treatment Period B:
−
Subjects allocated in Treatment Period B.
−
Subjects allocated and treated in Treatment Period B.
−
Subjects allocated in Treatment Period B but not treated and the reasons for not being 
treated.
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−
Treatment Period B completers.
−
Trial completers treated in treatment Period B.
−
Trial completers.
−
Subjects allocated and discontinued from IMP in Treatment Period B.
−
Subjects allocated and discontinued from the trial in Treatment Period B.
In addition, an overview table will be prepared presenting the number of subjects enrolled, 
allocated, in the SAF, and in the FAS per country and per site. Percentage calculation will be done 
in 2 ways: 
•
Denominator will be the number of all allocated subjects.
•
Denominator will be the number of allocated subjects in the respective country and site.
10.2
Subject discontinuations
Discontinuations from the trial and from IMP will be presented for the SAF overall, per country and 
per site. 
Reasons for discontinuations from the trial or from IMP will be presented for:
•
Subjects discontinued from the trial.
•
Subjects discontinued from IMP in Treatment Period A.
•
Subjects discontinued from IMP in Treatment Period B.
Percentage denominator will be the number of subjects discontinuing in the respective group.
The details for “other reasons” will be presented in a frequency table, if applicable.
If more than 10% of subjects in the SAF discontinue the trial, the distribution of the time to 
discontinuation from the trial will be summarized using time-to-event methods. Time will be weeks 
until discontinuation. 
10.3
Protocol deviations
Major protocol deviations will be presented overall and by site for the SAF. They will be grouped 
into categories as collected and summarized descriptively.
Major protocol deviations will be presented in a subject data listing sorted by site and treatment.
11
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
No statistical tests for comparison of demographic and baseline data between treatment groups will 
be performed.
Subject demographics and baseline characteristics will be summarized descriptively by treatment
group and overall. 
Subject demographics and other baseline characteristics will be descriptively summarized for the 
SAF and the FAS. Subject demographics will also be presented for the enrolled set; presentation 
will be without treatment group but only for overall.
Furthermore, the subgroups will be displayed as defined in Section 8.2.1.
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11.1
Subject demographics
Subject demographics are age [years], height [m], sex, race, ethnicity, and age group.
Age groups will be <18 years, ≥18 years and <65 years, ≥65 years and <85 years, and ≥85 years.
Remark:
Weight is recorded several times together with the vital signs parameters. Therefore, weight and the 
derived body mass index (BMI) will be described in the vital signs section below.
11.2
Other baseline characteristics
For parameters collected on more than 1 occasion during the trial including baseline, the assessment 
at baseline will be presented together with the assessments collected later in the trial rather than in a 
separate table for the baseline assessment only. These parameters are:
•
Efficacy outcome parameters, e.g., pain intensities (current, average, and worst).
•
Questionnaires and CRPS severity score (including signs and symptoms of CRPS).
•
Laboratory parameters.
•
Twelve-lead ECG parameters.
•
Vital signs parameters.
•
Bone turnover markers.
•
Soluble interleukin-2 receptor.
11.3
Subject medical history
11.3.1
Medical history
Diseases and surgical interventions are presented as “prior” or “concomitant” as documented by the 
investigator.
Medical history will be summarized and sorted alphabetically, separately for prior and concomitant 
diseases, by SOC and Preferred Term (PT). The number of subjects will be displayed for each SOC
and PT.
11.3.2
Dental history
Dental history will be summarized separately in the same way as the medical history.
Furthermore, the time since the last dental visit will be summarized.
11.3.3
Complex regional pain syndrome (CRPS) history
CRPS history will be descriptively summarized:
Continuous parameters based on date of Visit 1are:
•
Time since inciting or precipitating event (month) – if unknown presented as unknown.
•
Time since onset of CRPS symptoms (month).
•
Time since diagnosis of CRPS (month).
Categorical baseline characteristics are: 
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•
CRPS type (Type I, Type II, Unknown).
•
CRPS etiology.
−
Inciting or precipitating event (Missing, Known, Unknown).
−
Fracture, Sprain, Surgery, Crush, Others.
•
CRPS location (Left Body Site, Right Body Site, Upper Extremity, Lower Extremity, more
than 1 Limb affected).
•
CRPS family history.
−
CRPS family history (No, Yes, Unknown).
−
Same limbs (No, Yes, Unknown).
•
Imaging method (None, Unknown, X-rays, Magnetic resonance imaging (MRI), Triple-
phase bone scintigraphy, Other).
Except for inciting or precipitating event and family history multiple answers are possible.
11.4
Prior and concomitant medication or therapy
Prior and concomitant therapies will be descriptively summarized by category of additional 
therapy/treatment. Assessment of prior and concomitant will be done as described in the following 
for medications.
Prior and concomitant medication is collected in the e-CRF as per enrollment. For the analysis, the 
following algorithm will be used to define prior and concomitant medication:
•
Prior is all medication stopped prior to the first dose of IMP, regardless of its start date. 
•
Concomitant is any medication not stopped before the first dose of IMP, regardless of its 
start date or medication started after the first dose of IMP.
Medication will be summarized and sorted alphabetically separately for prior and concomitant 
medication by Anatomical Therapeutic Chemical categories (Level 2: pharmacological or 
therapeutic subgroup and Level 3: chemical or therapeutic or pharmacological subgroup). 
For each medication, the number of subjects will be displayed. 
Medication or therapy started after last dose of IMP will be flagged in the subject data listing.
In addition, all newly prescribed opioid analgesic medication will be separately summarized overall 
and up to Week 26. Furthermore, the time to first newly prescribed opioid analgesic medication
after first IMP will be summarized using time-to event methods. A newly prescribed opioid 
analgesic medication is any medication that is started after first IMP.
12
EXPOSURE AND COMPLIANCE
Exposure and compliance will be descriptively summarized for the SAF.
12.1
Exposure
Exposure will be displayed for both treatment periods as the number of subjects receiving 1,2,3 or 
4 infusions. It will be descriptively summarized. For percentage calculation, the denominator will 
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be the number of subjects in the FAS for the Treatment Period A. For the Treatment Period B, the 
denominator will be the number of subjects treated in Treatment Period B.
In addition, 2 further overviews will be generated. 
First the number of subjects with a planned reduced dose will be summarized. Those subjects are 
identified if the eCRF entry “Volume of drug transferred into the infusion bag” is not 8 mL.
Denominator usage as described above. 
Secondly, the number of subjects with a completely and not completely administered dose will be 
displayed. The display will be done by day for Treatment Period A (Day 1, Day 4, Day 7, Day 10) 
and visit for Treatment Period B (Visit 11, Visit 12, Visit 13, Visit 14). For percentage calculation,
the number of subjects with an administered drug for that day/visit will be used.
12.2
Compliance
Compliance will be assessed for each visit. Compliance (%) to IMP administration will be set to 
100%, if the dose was completely administered. Otherwise, compliance (%) will be calculated as 
the ratio of the approximate value administered, divided by the planned dose (500 mL).
Moreover, the cumulative compliance per treatment period will be derived as the ratio of the actual 
cumulative dose divided by the planned cumulative dose.
Compliance and cumulative compliance will be descriptively summarized.
13
EFFICACY ANALYSES
13.1
Primary endpoint
13.1.1
Average pain intensity (recorded in the eDiary)
The primary efficacy variable is the change from baseline to Week 12 in the average pain intensity 
score. The average pain intensity score is calculated as the weekly average of the pain intensities
recorded daily (in the evening) in the electronic diary with a 24-hour recall period.
The average pain intensity score for Week x is based on the respective 24-average pain intensity 
scores recorded daily in the electronic diary during week x, i.e. 7-day intervals starting Day 1 to 
Day 7 for Week 1, and Day 8 to Day 14 for Week 2, etc.
For the average pain intensity score for Week x, all available values in Week x will be used, no 
imputation will be done for missing scores. If no pain scores are available for a week, the weekly 
mean for that patient and week will remain missing. E-Diary data beyond Day 84 will not be used 
for the analysis but be part of the subject data listing. Subjects in the FAS without baseline value 
and subject without any weekly average pain intensity subject be imputed with zero as change from 
baseline and for the baseline value imputation will be done as the average baseline value of the 
treatment arm.
Baseline is calculated as the mean of the average pain intensity score recorded daily in the 
electronic diary during the baseline phase (Day -7 to Day -1).
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13.1.2
Main analysis
For the primary objective of the trial, the primary estimand is the difference in means of the primary 
efficacy endpoint of 400 mg intravenous neridronic acid compared to placebo for all allocated and 
treated subjects. This treatment policy or de facto estimand measures the effect of neridronic acid 
regardless of adherence to treatment or protocol.
The primary estimand will be estimated by the analysis of the primary efficacy endpoint for the Full 
Analysis Set. The primary analysis will fit a mixed model repeated measurement (MMRM) to the 
change from baseline in the average pain intensity scores from Week 1 to Week 12 recorded once 
daily in the electronic diary, including the covariate baseline pain intensity score, and the factors 
geographic region, week, treatment, and treatment-by-week interaction as fixed effects, and subject 
as random effect. An unstructured covariance matrix will be used to model the covariance structure, 
degrees of freedom will be estimated using the Kenward-Roger approximation.
The primary efficacy analysis will be performed using the contrast, i.e., the mixed model Wald test, 
of neridronic acid 400 mg versus placebo at Week 12 of the treatment, week and treatment-by-week 
interaction term of the mixed effects model described above. Model-based parameter estimates
(least square means), standard errors, 95% confidence intervals, and p-values will be tabulated. This 
analysis will be performed using only the observed values without imputation of missing values.
If the default Newton-Raphson algorithm used by statistical analysis software (SAS) PROC 
MIXED fails to converge, the Fisher scoring algorithm up to iteration 2 will be used (via the 
SCORING=2 option of the PROC MIXED statement) to obtain the initial values of covariance 
parameters (Mallinckrodt et al. 2008). If this alternative also fails to converge, then in addition the 
no-diagonal factor analytic structure (via the TYPE=FA0(T) option of the REPEATED statement, 
where T=12 is the total number of weeks in the 12-week trial period) will be used, which 
effectively performs the Cholesky decomposition of the covariance matrix and is numerically more 
stable. The first algorithm that leads to convergence in this sequence of fallback measures will be 
the algorithm used for the primary analysis of the trial.
A descriptive summary of the weekly averages and the changes from baseline will be generated by 
treatment group. 
A graphical plot of the model-based estimates and the 95% CI of the change from baseline of the 
average pain intensity scores over the 12-week trial period will be created. Both treatments will be 
presented in one plot by week. 
13.1.3
Sensitivity analysis
Additional sensitivity analyses will be performed to assess the robustness of primary analysis 
results with respect to handling of missing data. Sensitivity analyses will include the imputation of 
missing pain intensity scores using different pattern mixture models (PMMs).
Diligent attempts will be made to limit the amount of missing data in the primary efficacy endpoint. 
Efforts will be made to follow-up subjects who discontinue treatment and to collect the primary 
efficacy endpoint for the statistical analysis.
Missingness assumptions – considerations
The primary analysis using the MMRM is based on the Missing at Random (MAR) assumption. For 
the treatment policy or de facto estimand, the MAR assumption is justified for neridronic acid 
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owing to the long half-life in bone and the anticipated persistent effect over the 12-week trial 
period. It can be assumed that the effect of neridronic acid continues after the treatment period is 
completed, and it also persists after the treatment period regardless of trial completion or early 
discontinuation. Therefore, the response of discontinued subjects will not change if the subjects 
continue to receive the stable therapy that they receive during the 12-week trial period up to Visit 8. 
If subjects change their treatment after discontinuation from the trial, it is nevertheless reasonable to 
assume that their response is not significantly altered as there are currently no established effective 
treatments. Hence, the MAR assumption is considered a plausible missingness mechanism for the 
primary estimand in the case of neridronic acid.
The MAR assumption cannot be verified based on data observed in the trial. Deviations from MAR 
cannot be excluded and several plausible missing not at random (MNAR) assumptions will be 
investigated to assess their impact. MNAR assumptions will be defined via pattern mixture models 
(PMM) specifying the distribution of missing values, e.g., for subjects discontinuing before the end 
of the trial. Plausible PMMs for the primary estimand are placebo multiple imputation (PMI) and 
the delta shift method. 
PMI is a reference-based approach based on the copy reference method. It models the means of 
missing values in the active arm based on the means observed in the placebo arm (reference arm). 
The method assumes that the response of discontinued subjects in the active arm gradually 
approaches the response in the placebo arm and eventually no effect of neridronic acid persists after 
a subject discontinues. For neridronic acid this appears conservative in light of the anticipated 
persistent effect.
The delta shift method models the means of missing values in the active arm by adding a pre-
specified value Δ to the observed means in the active arm. The method includes a tipping point 
analysis, which is defined as the delta that must be added in order to overturn conclusions from the 
primary analysis from statistically significant to statistically insignificant. The method assumes that 
discontinued subjects in the active arm have higher pain compared to subjects who stay in the trial. 
Again this seems conservative if persistence of effect can be assumed for neridronic acid.
Overall, the 2 PMMs can be considered more conservative than MAR because they model missing 
pain intensity scores in the active arm using higher mean values than the means actually observed, 
whereas the placebo arm is not changed. In this way, neridronic acid is effectively penalized under 
these assumptions. 
In summary, for neridronic acid the MAR assumption seems to be the most plausible missingness 
assumption for analyses estimating the primary estimand. It will be supplemented by sensitivity 
analyses based on MNAR assumptions representing plausible and reasonably conservative 
deviations from MAR.
Sensitivity analysis
Sensitivity analyses will be conducted with two imputation methods followed by an analysis of 
covariance (ANCOVA) model. The ANCOVA model will be fitted to the change from baseline in 
the average pain intensity scores at Week 12 recorded once daily in the electronic diary, with the 
covariate baseline pain intensity score, and the factors geographic region and treatment as fixed 
effects.
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The results of the primary analysis and both sensitivity analyses will be summarized numerically 
and graphically in a forest plot, presenting the number of subjects, model estimates and 95% CIs of 
the treatment differences to placebo for both active doses.
The primary efficacy analysis will use the observed values of the primary efficacy endpoint without 
any imputations. To perform the sensitivity analyses for the primary analysis, weekly average pain 
intensities of the primary efficacy endpoint will be imputed until Week 12. 
In the following the concept of PMM will be described as well as the details on the specific PMM 
imputation information for PMI and the delta shift method.
Pattern mixture models
Subjects dropping out will be classified into patterns according to the week they discontinue from 
the trial. In each pattern, the distribution of missing values conditional on observed values is 
determined based on the imputation method used and imputations are drawn from the modified 
distribution.
The pattern mixture model framework (e.g., Verbeke and Molenberghs 2009) will be implemented 
using multiple imputation. Multiple imputation comprises 3 separate steps:
1.
Impute: Generate M completed datasets (week 1 to week 12) drawing imputed values from the 
pattern-specific distributions. In total M = 200 imputations will be generated. This is in line 
with recommendations in Carpenter and Kenward (2013).
2.
Analyze: Analyze the M completed datasets individually (analysis via ANCOVA). 
3.
Combine: Combine the results from the M individual analyses into a single result using Rubin’s 
rules (Little and Rubin 2002).
The imputation model will be based on the Markov chain Monte Carlo (MCMC) method for 
general patterns of missingness (Dmitrienko et al. 2005).
The imputations step 1. is described for both PMM used in this trial in the below with the specific 
imputation used.
All missing values will be imputed in the same way, i.e., no differentiation between intermittent 
missing values and missing values after dropout is made. Missing values will be imputed for all 
12 weeks.
Placebo Multiple Imputation
The Placebo Multiple Imputation method draws imputations in all treatment arms based on the data 
observed in the placebo arm. In each pattern, the distribution of missing values conditional on 
observed values is defined for all arms by the corresponding distribution from the placebo arm. The 
imputation step will be performed as follows:
a.
Estimate M sets of parameters for the pattern specific reference distribution from the 
placebo arm. All M parameter datasets will be stored in an analysis dataset.
b. Generate M completed datasets for all treatment arms using the M sets of parameters from 
step 1. All M imputed datasets will be stored in an analysis dataset.
Delta Shift Method
The Delta Shift Method is based on the observed distribution and shifts the observed means at the 
time points after dropout by a pre-specified value. In each pattern, the distribution of missing values 
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conditional on observed values is based on the shifted means, and imputations are drawn from the 
modified distribution. This approach models a diminishing placebo effect after a subject drops out. 
The sensitivity analysis will use different values for the shift parameter Δ. Delta will start with 0 
and be increased by 0.1 points until the tipping point has been reached. The tipping point is defined 
as the delta that must be added in order to overturn conclusions from the primary analysis from 
statistically significant to statistically insignificant. Starting with 0 enables to evaluate MI under the 
MAR assumption.
The shift parameter is constant, i.e., the same shift parameter will be used for all treatment arms, for 
all times after dropout, and for all patterns. Based on this, the imputation step will be performed as 
follows:
a.
Estimate M sets of parameters of the linear model. All M parameter datasets will be stored in 
an analysis dataset.
b. Generate M completed datasets using the M sets of parameters from step 1.
c.
Modify the completed datasets by adding a shift Δ to each imputed value. All M imputed 
datasets will be stored in an analysis dataset. 
All missing values will be imputed in the same way, i.e., no differentiation between intermittent 
missing values and missing values after dropout is made.
13.2
Secondary endpoints
All secondary efficacy endpoints will be analyzed for the Full Analysis Set.
Descriptive summaries will be generated for all visits where data is assessed as per schedule of 
events in Section 1.7 of the protocol. Analysis will be presented per visit and treatment if not 
specified differently.
13.2.1
Average pain intensity (recorded on tablet computer)
The change from baseline in the average pain intensity, recorded on the tablet computer, will be 
analyzed with an MMRM, including the covariate baseline pain intensity score, and the factors 
geographic region, week, treatment, and treatment-by-week interaction as fixed effects, and subject 
as random effect. An unstructured covariance matrix will be used to model the covariance structure.
The analysis will be performed using the contrast, i.e., the mixed model Wald test, of 400 mg 
neridronic acid versus placebo at Week 26 of the treatment, week and treatment-by-week 
interaction term of the mixed effects model described above. Model-based parameter estimates, 
standard errors, 95% confidence intervals, and p-values will be tabulated. This analysis will be 
performed using the observed values without imputation of missing values.
13.2.2
Pain response to treatment (recorded on tablet computer)
Pain response to treatment, defined as an at least 30% decrease from baseline in average pain 
intensity, recorded on the tablet computer, will be derived. If a subject shows a worsening or the 
pain intensity score for the respective visit is missing, then the subject will be considered a pain 
non-responder for the respective visit. A logistic regression model will be fitted to the data, 
including the covariate baseline pain intensity score, and the factors geographic region and
treatment as fixed effects. Model-based parameter estimates, standard errors, 95% confidence 
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intervals, and p-values for the odds ratio at Week 12 and Week 26 between 400 mg neridronic acid 
and placebo will be tabulated.
The analysis of pain response to treatment will include a cumulative responder analysis at Week 12, 
Week 26, and Week 52, where responder rates will be calculated for different percentage thresholds 
for decrease from baseline in average pain intensity. The evaluation of Week 52 assessments is part 
of other data that is collected but due to similar analyses described together with secondary 
endpoint evaluations at Week 12 and Week 26.
The percentage decrease from baseline in average pain intensity, recorded on the tablet computer, 
will be derived per subject as
%pain decrease = Baseline Pain Intensity - average pain intensity Week 
Baseline Pain Intensity
× 100
with  being Week 12, Week 26, and Week 52 respectively.
The responder rate for a given percentage threshold is defined as the proportion of subjects with a 
% pain decrease equal to or above the percentage threshold, i.e. the 30% responder rate (30% 
responder) is the percentage of subjects with at least 30% pain decrease. The distribution (by 
changing the percentage threshold) of responder rates in a given week will be determined for each 
treatment group using percentage thresholds of 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100. 
Descriptive statistics will be displayed for those percentage thresholds as well as for non-
responders.   
In addition, 30% responders and 30% non-responders (subject who show a worsening or for whom 
the pain intensity score is missing and subjects with pain decrease <30%) will be displayed for 
Week 12, Week 26, and Week 52.
A graphical presentation for Week 12, Week 26 and Week 52 of the proportion of subjects defined 
as responders by treatment (y-axis) versus the threshold value (continuous scale) used to define a 
response (x-axis) will be produced. The 30% reduction as well as the 50% reduction will be 
indicated by vertical lines. 
13.2.3
Dynamic mechanical allodynia
For a detailed description of the dynamic mechanical allodynia assessment please see protocol 
Section 12.3.2. Allodynia is rated on an 11-point NRS and assessed 5 times. A value of “10” 
corresponds to the individual maximum pain imaginable. The degree of pain sensitivity is 
calculated by the geometrical mean of the five pain ratings given (Maier et al. 2010). 
The change from baseline in the DMA will be analyzed using a similar model as for average pain 
intensity. Only subjects with allodynia at baseline, i.e., a DMA score greater than 0 on the 0 to 10 
NRS, will be included in the analysis.
In addition, descriptive summaries will be generated for the degree of pain sensitivity and displayed 
together with the respective changes from baseline.
13.2.4
Pressure pain threshold
For a detailed description of the pressure pain threshold please see protocol Section 12.3.2. Pressure 
pain threshold will be measured at both the affected and unaffected limb for all subjects. 
Measurements are repeated in 3 series of slowly increasing stimulus intensities and the respective 
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pressure pain threshold is documented. For the final PPT, the arithmetic mean of all 3 consecutive 
measurements is calculated (Rolke et al. 2010, Mainka et al. 2014). 
The ratio of the thresholds of the affected and the unaffected (denominator) limb will be calculated.
The change from baseline in the ratio of the PPT in the affected limb to the PPT in the unaffected 
limb for the thenar muscle/abductor hallucis muscle will be analyzed using a similar model as for 
average pain intensity. Only subjects with deep somatic pain (PPT 300 kPa) in the affected limb at 
baseline will be included in the analysis.
In addition, descriptive summaries will be generated for the ratio of the thresholds as well as for the 
changes from baseline.
13.2.5
Edema
For a detailed description of the Edema measurement, please see protocol Section 12.3.4. Edema 
will be measured at both the affected and unaffected limb for all subjects having edema as a 
positive CRPS sign at baseline (based on clinical judgment; sign “Asymmetric edema” ticked “yes” 
on the CRPS Severity Score at Visit 2). Each measurement of the limbs will be performed 3 times. 
The average of the 3 measurements will be used for further analysis.
The ratio of the averages of the affected and the unaffected (denominator) limb will be calculated.
The change from baseline in edema will be analyzed using a similar model as for average pain 
intensity. Only subjects with presence of the CRPS sign “asymmetric edema” at baseline will be 
included in the analysis.
In addition, descriptive summaries including changes from baseline will be generated for the 
averages of the affected and the unaffected limb and the ratio of the two averages.
13.2.6
Confirmatory testing strategy for secondary endpoints
A confirmatory testing procedure will be used for testing of the superiority of neridronic acid 
400 mg versus placebo with respect to the primary and selected secondary efficacy endpoints 
(change from baseline to Week 26 in the average pain intensity, change from baseline to Week 12 
in the pain intensity level of DMA, change from baseline to Week 12 in the PPT ratio, and change 
from baseline to Week 12 in the ratio of figure of eight measurements).
First, the primary endpoint will be tested at a one-sided level α = 2.5%. If the first test is statistically 
significant, the 4 secondary endpoints will be tested in a second stage.
To control for the family-wise type I error rate at the one-sided 2.5% level, a hybrid Hochberg-
Hommel step-up procedure (hybrid-0 procedure in Gou et al. 2014) will be applied. The testing 
procedure uses the ordered p-values p(1) ≥ p(2) ≥ p(3) ≥  p(4). At first, if the largest p-value p(1) ≤ α, 
then all 4 hypotheses are rejected. Otherwise the associated null hypothesis H(1) is accepted and 
testing proceeds to the next step. In general, at Step i = 2,..4, if p(i) ≤ciα, then any hypothesis with 
p-value ≤ diα will be rejected and testing stops; otherwise, the null hypothesis H(i) is accepted and 
testing continues at the next step. At Step 4, the null hypothesis H(4) is rejected if p(4) ≤ α/4; 
otherwise H(4) is accepted. The constants used in the testing procedure are defined by ci = (i+1)/(2i)
and di = 1/i and are given in the table below.
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I
1
2
3
4
ci
1
3/4
2/3
5/8
di
1
1/2
1/3
1/4
This semiparametric multiple testing procedure controls the family-wise error rate in the strong 
sense if the test statistics follow a multivariate normal distribution with non-negative correlation 
coefficients (Gou et al. 2014) which can be assumed for the investigated 4 efficacy endpoints.
13.3
Other efficacy data
To assess the efficacy of neridronic acid in subjects with CRPS other data is collected as described 
in Section 1.2 of the protocol and will be analyzed as described in the following chapters.
Descriptive summaries will be generated for all visits where data is assessed as per schedule of 
events in Section 1.7 of the protocol. Analysis will be presented per visit and treatment if not 
specified differently.
13.3.1
Pain Intensity recording on the tablet computer.
Analysis will be performed by descriptively summarizing average, worst and current pain intensity 
recorded on the tablet computer by visit and treatment group. In addition, changes from baseline 
and changes from Week 26 will be displayed. The value at Visit 2 is considered as baseline value.
Graphical display of the worst and current pain recording by visit and treatment will be done in 
addition to the primary endpoint graphical display of the average pain intensity recordings.
In addition, analysis will be repeated for subgroups defined by subjects who are treated in 
Treatment Period B in combination with the responder definition based on duration of response as 
defined in Section 13.3.2.
13.3.2
Pain response based on pain intensity recordings on the tablet computer
Pain response to treatment based on pain intensity recordings on the tablet computer will be 
analyzed based on the comparison timepoint, either baseline or Week 26.
Pain response as % decrease from baseline
Analyses are covered as part of secondary endpoint “Pain response to treatment” (see 
Section 13.2.2). In addition to the 30% responders and 30% non-responders a display with regards 
to the percentage threshold of 50% will be done. A 50% responder is a subject showing at least 50% 
pain decrease and a 50% non-responder being a subject with a missing pain intensity or a subject 
having less than 50% pain decrease.
Pain response as % decrease from Week 26
Descriptive statistics will be displayed for % decrease from Week 26 analogously to analysis of 
pain response as % decrease from baseline. This will be done using the pain intensity at Week 26 
instead of baseline pain intensity for determination of the % decrease. 
Duration of effect – Response based on duration of effect
The duration of effect for treatment period A is defined as the time from baseline to first loss of 
response. Response is defined as at least 30% decrease from baseline and first loss of response is 
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the first time after achieving response that a subject shows less than 10% decrease from baseline. 
Duration of effect is then the time from baseline till the last timepoint before first loss of response. 
Pain assessments (tablet computer) that are considered for this analysis are those at Day 1 
(Baseline), Week 6, Week 12, Week 16, Week 22 and Week 26. 
Subjects never reaching a 30% decrease from baseline will have a duration of effect of 0 weeks. 
Subjects reaching a 30% decrease from baseline but showing no loss of effect, i.e. not dropping to 
below 10% decrease from baseline afterwards, will be censored at Week 26 with a duration of 
effect of 26 weeks. Else the duration of effect is taken as the last assessment a subject shows an 
effect (at least 30% response) before first experiencing a loss of response. e.g., if subject shows less 
than 30% decrease at Week 6, at least 30% decrease at Weeks 12 and 16 and at Week 22 less than 
10% decrease, the duration of effect is set to 16 weeks.
Duration of effect will be analyzed using survival analyses with timepoints respective to the visits 
where pain is assessed on the tablet computer. A frequency table for the duration of effect will be 
provided for Follow-Up Period 1.
Furthermore, to assess the effect of a second treatment cycle, for those subjects who received two 
treatment cycles of neridronic acid, descriptive statistics for the change in average pain intensity 
from baseline, the change in average pain intensity from Week 26 and pain response as % decrease 
from baseline and from week 26 will be displayed for Follow-up Period 2 for the following 
responder subgroups based on duration of effect.
•
Never-responders: subjects with a duration of effect = 0 weeks.
•
Lost-responders: Subjects with a duration of effect <26 weeks.
•
Responders: subjects with a duration of effect =26 weeks.
13.3.3
Pain intensity recording in the electronic diary
Analysis and display of average pain recorded in the electronic diary is described in Section 13.1.1). 
Derivation and analysis of worst and current pain intensities  recorded in the electronic diary will be 
done in the same manner.
13.3.4
Active range of motion (AROM) 
For a detailed description of the AROM please see protocol Section 12.3.5. 
For subjects having decreased AROM at baseline (diagnosed based on clinical judgment; sign 
“Motor abnormalities” ticked “yes”, sub-category “decreased AROM” ticked “yes” on the CRPS 
Severity Score at baseline), both affected and unaffected limbs will be measured. 
The AROM in each of the unaffected and affected limbs will be measured 2 times, the AROM 
consists of two components flexion and extension, the sum of both builds the AROM. The results of 
both measurements and both components will be documented; only the best performance of the 
2 repetitions will be used for further analysis, i.e. the highest flexion and the highest extension value 
per limb will be added and used further.
The ratio of the AROM of the affected and the unaffected (denominator) limb will be calculated.
Descriptive summaries including changes from baseline will be generated for the AROM of the 
affected and the unaffected limb and the ratio of the two. The summaries will distinguish between
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the CRPS locations and display results for upper extremity and lower extremity as well as left and 
right body site separately.
13.3.5
CRPS Severity Score 
The signs and symptoms of CRPS are recorded using tablet computers. The investigator examines 
the signs. The subject reports his/her symptoms with a recall period of 48 hours. At the Enrollment 
Visit, patients record their symptoms with recall period since onset of CRPS. 
To derive the CRPS severity score, the symptoms reported with recall period 48 hours will be used.
Subjects will be queried on 8 self-reported symptoms (queried YES or NO): 
1.
continuing, disproportionate pain; 
2.
allodynia and/or hyperalgesia; 
3.
temperature asymmetry; 
4.
skin color asymmetry; 
5.
sweating asymmetry; 
6.
edema; 
7.
dystrophic changes; 
8.
motor abnormalities. 
Moreover, subjects will be examined for 8 signs (observed on examination, queried YES or NO): 
1.
hyperalgesia to pinprick; 
2.
allodynia; 
3.
temperature asymmetry by palpation; 
4.
skin color asymmetry; 
5.
asymmetric edema; 
6.
sweating asymmetry; 
7.
dystrophic changes; and 
8.
motor abnormalities.
Each sign or symptom is assigned a dichotomous value (1 = presence; 0 = absence). The resulting
CRPS severity score ranges from 0 to 16, with higher scores indicating greater CRPS severity. If 
one of the 16 signs and symptoms is missing the CRPS severity score will not be calculated and is 
considered missing.
A descriptive summary will be created by sign/symptom and visit (recall period 48 hours), 
A graphical display over the entire trial will be created for the proportion of subjects with a 
sign/symptom, for each of the signs and symptoms, all treatments will be presented in one plot. 
Furthermore, a descriptive summary of the continuous CRPS severity score and the corresponding 
change from baseline will be generated. A graphical plot of the means and 95% CI of the CRPS 
severity score over time will be created. All treatments will be presented in one plot. Assessments at 
visit 2 are considered baseline assessments.
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13.3.6
Patient Global Impression of Change (PGIC)
The observed values of the PGIC will be summarized descriptively (categorical). Furthermore, the 
following categories will be pooled and presented:
•
‘very much improved’ and ‘much improved’
•
‘much worse’ and ‘very much worse’
•
‘very much improved’ and ‘much improved’ and ‘minimally improved’.
•
‘no change’ and ‘minimally worse’ and ‘much worse’ and ‘very much worse’ 
13.3.7
Patient Global Impression of Severity (PGI-S).
The observed values of the PGI-S will be summarized descriptively (categorical) and shift tables 
with regards to the baseline assessment will be generated. In addition, a shift table between 
Week 52 and Week 26 will be produced.
13.3.8
EuroQoL-5 Dimension-5 level (EQ-5D-5L)
The EQ-5D-5L has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each of the 5 dimensions has 5 possible levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. 
The health state of the subject is coded by the vector of the reported levels in each of the 
5 dimensions. An EQ-5D-5L Health Status Index will be derived from the 5-dimensional health 
status vector using a lookup table that can be downloaded from the website of the EuroQol group. 
The index set provided for the US in the spread sheet “EQ-5D-5L value sets” of the Excel file “EQ-
5D-5L_Crosswalk_Value_Sets.xls” will be used to assign an index value to the health status vector 
of a subject. For the US general population, the possible EQ-5D-5L index scores range from -0.109 
for the health status vector “55555” to 1.0 for the vector “11111” on a scale where an index value of 
0.0 represents death and 1.0 represents perfect health. 
The EQ-VAS ranges from 0 (worst imaginable health) to 100 (best imaginable health).
A descriptive summary of the 5 categorical EQ-5D-5L dimensions will be generated by dimension, 
and visit. Furthermore, a descriptive summary of the continuous EQ-5D-5L index and the EQ VAS, 
and the corresponding changes from baseline will be generated by visit. In addition, for Week 52 
the change to Week 26 will be generated.
13.3.9
PROMIS-29 profile and PROMIS-EDDEP39
The Patient-Reported Outcomes Measurement Information System (PROMIS-29®) profile assesses 
7 domains, i.e., depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, 
and ability to participate in social roles and activities, each with 4 questions and a recall period of 
7 days (Cella et al. 2007).
In addition, suicidal ideation will be assessed using the PROMIS-EDDEP39, which is Question 
EDDEP39 of the PROMIS Item Bank version 1.0 – Emotional Distress – Depression (Pilkonis et al. 
2011).
The following description can be found in the PROMIS – Adult Profile Instruments (2015).
Each question has five response options ranging in value from 1 to 5, except for the Pain Intensity 
item (Question number 29 [GLOBAL07]) which has eleven response options ranging in value from 
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0 to 10. A raw score is created from each domain that makes up the Profile. To find the total raw 
score for a domain with all questions answered, the values of the response to each question within
the domain is summed up. For example, for the 29-item Profile, the lowest possible raw score 
within Anxiety is 4 (a score of 1 on all four items); the highest possible raw score is 20 (see all short 
form scoring tables in Appendix). 
Descriptive summaries including changes from baseline for the domains will be generated.
Question number 29 (GLOBAL07) will be descriptively summarized and changes from baseline 
will be calculated for Week 16 and Week 22 only
The Question EDDEP39 of the PROMIS Item Bank version 1.0 – Emotional Distress – Depression 
(PROMIS-EDDEP39) will be descriptively summarized. A shift table will be generated to display 
changes from baseline.
13.3.10
Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2) - 6 neuropathic 
items
The SF-MPQ-2 is a single measure of the major symptoms of both neuropathic and non-
neuropathic pain. The pain qualities will be assessed using the 6 neuropathic items from the 
SF-MPQ-2. A total score for the neuropathic subscale will be calculated as a mean of all 
6 neuropathic items (Gauthier et al. 2014).
Subjects will be asked to consider and report only the pain related to the CRPS when completing 
the instrument using the tablet computers maintained at the sites.
Descriptive summaries including changes from baseline will be generated for the neuropathic total 
score as well as for each of the 6 individual items.
13.3.11
Pain Catastrophizing Scale (PCS)
The PCS will be used as a measurement tool to capture pain catastrophizing; the scale will be 
completed by the subjects using the tablet computers.
Derivation and details on the analysis of the PCS is described in detail in the User Manual of the 
PCS (Sullivan et al. 2009). The PCS is a 13-item instrument asking subjects to indicate the degree 
to which they experienced each of 13 thoughts or feelings when experiencing pain, on 5-point 
scales with the end points (0) not at all and (4) all the time. The PCS yields a total score. The PCS 
total score is computed by summing responses to all 13 items and ranges from 0 – 52. 
Descriptive summaries including changes from baseline will be generated for the total score.
13.3.12
Pain Self Efficacy Questionnaire (PSEQ).
Ten items were selected to reﬂect a wide variety of classes of activities and tasks. Respondents 
consider how confident they are performing each activity, while taking their pain into account. Each 
activity is rated by selecting a number on a 7-point scale, where 0 equals ‘‘not at all conﬁdent’’ and 
6 equals ‘‘completely conﬁdent’’. A total score is calculated by summing the scores for each of the 
10 activities, yielding a maximum possible score of 60. Higher scores reﬂect stronger self-efficacy 
beliefs (Nicholas 2007). The Total Score will be displayed by descriptive summaries including 
changes from baseline.
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13.4
Health economic and work productivity data
13.4.1
Work Productivity and Activity Impairment Questionnaire: CRPS 
(WPAI: CRPS). (US sites only)
History of CRPS including impairments of personal activities, both work-related (e.g., 
absenteeism/presenteeism) and non-work-related will be captured using the WPAI: CRPS.
Descriptive summaries will be generated for all questions and displayed by treatment and week.
13.4.2
Medical resources utilization. (US sites only)
Medical resource utilization and health economics data will include information regarding 
hospitalization, emergency room visits, nursing home stays, health care provider (other than trial 
investigator) contacts, home services, home help, and special devices used due to CRPS-related 
symptoms and pain. 
The responses to the questions will be documented on paper and stored as part of the source data. 
Data will be transcribed into the eCRF by the investigator or delegated site staff.
Descriptive summaries will be generated by treatment and visit.
Parameters summarized are:
•
Healthcare Utilization domain (No, Yes):
−
Hospitalization during past 12 weeks (if yes, number of times).
−
Emergency room treatment (no hospitalization) (if yes, number of times).
−
Nursing Home Stay (if yes, number of nights).
−
Health Care providers (multiple answers possible) (if yes, number of visits and number 
of phone calls).
•
Home Service, Home Help, Formal and Information Caregiving, Devices
−
Home Services and Help (multiple answers possible) (if yes, number of times and 
average duration (min))

Cleaning services.

Meals delivered.

Formal childcare assistance.

Transportation.

Caregiving.
−
Special Product/Device/Tool

Special equipment/assistive tools.
14
ANALYSIS OF PHARMACOGENETIC DATA, OMICS DATA AND 
PHARMACOKINETIC AND PHARMACODYNAMIC 
PARAMETERS
All measurements and analyses of pharmacogenetics data and omics data will be described in 
separate analysis plans.
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All measurements and analyses of pharmacokinetic and pharmacodynamic parameters will be 
described in separate pharmacometric analysis plans.
14.1
Analysis of plasma concentration
In this trial, plasma concentrations of the following analytes will be investigated: the parent 
compound neridronic acid. Analysis will be performed on the PKS.
Plasma concentration data will be displayed with descriptive statistics including the coefficient of 
variation, the geometric mean and geometric coefficient of variation as defined in Section 19.1.5 at 
each scheduled time point and for each analyte. Missing data will be shown as a separate category 
in the summary tables. The individual data will be displayed in the subject data listings.
Descriptive statistics of the concentrations will only be determined if at least 75% of the 
observations at a given sampling point have quantifiable results which have not to be excluded due 
to the deviation rules. Data excluded from the descriptive statistics will be shown in brackets (e.g.,
like [<LLOQ] or with the measured value like [32.3]) in the respective listings. 
Missing data will be treated as such and will not be imputed or replaced in any way if not specified 
otherwise. 
14.2
Bone turnover markers and markers for disease severity or CRPS 
progression
Bone turnover markers will be analyzed in the PDS. Soluble interleukin-2 receptor (sIL-2R) will be 
analyzed in the SAF.
The following bone turnover markers are assessed:
•
Bone formation markers:
−
Procollagen type I amino-terminal propeptide (PINP).
−
Bone alkaline phosphatase (BAP).
•
Bone resorption marker:
−
C-terminal telopeptide of type I collagen (CTX).
All bone turnover marker data will be listed in a subject data listing.
Bone turnover marker values as well as sIL-2R values, including changes from baseline, will be 
descriptively summarized by parameter and time point. Baseline is defined by the value on Day 1 
(Visit 2).
For bone turnover markers as well as sIL-2R values a graphical plot of the mean and 95% CI of 
bone turnover marker values over time will be presented. Similarly, a plot of the mean change from 
baseline of bone turnover marker values over time will be presented. Furthermore, a display by 
fasting and non-fasting status will be done as assessed on the ‘Date of confirmed Visit’ in the 
eCRF. The non-fasting status consists out of non-fasting, insufficient fasting and unknown 
categories.
All bone turnover marker data and sIL-2R data will be listed in a subject data listing.
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15
SAFETY ANALYSES
No statistical tests for comparison of safety data between treatment groups will be performed.
Safety data will be summarized descriptively by treatment group and by visit if applicable.
All safety data will be presented for the SAF unless otherwise specified.
The interim integrated clinical trial report will report all safety data until the cut-off date (last 
subject performing its Visit 11 (Week 26)), regardless of whether data is assessed before or after 
Visit 11. 
15.1
Adverse events
A treatment emergent adverse event (TEAE) is defined as any adverse event that based on start date 
and start time information occurs in the on-treatment-period as defined in Section 8.2.2.
A pre-treatment non-TEAE is an adverse event starting in the pre-treatment period as defined in 
Section 8.2.2.
If there are partial dates or times, an adverse event will be considered treatment emergent unless the 
information available will clearly exclude it. Further details can be found in Section 19.1.6.1.
Assignment of TEAEs to treatment will be based on the definition of the on-treatment-period given 
in Section 8.2.2, thus, TEAEs occurring during the on-treatment period are assigned to the 
respective treatment. TEAEs will be assigned to treatment based on their start date. 
Display by trial phase refers to a display by:
•
Treatment Period A/Follow-up Period 1.
•
Treatment Period B/Follow-up Period 2.
For display by trial phase TEAEs starting in the Follow-Up Period 2 will be displayed within one of 
the four treatment groups according to their treatment schedule in Treatment Period A and B.
Display for Treatment Period B/Follow-up Period 2 will in addition to the four treatment groups 
include a neridronic acid overall group combining all subjects that have received a dose of 
neridronic acid.
For adverse events where the intensity changes over time, the maximum intensity observed during 
the whole duration of the adverse event will be documented. 
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The causal relationship of TEAEs to IMP is categorized as follows: 
Category
Assessment by investigator
Related
certain 
probable/likely
possible
Not related
unlikely
not related 
Unknown
unassessable/unclassifiable
conditional/unclassified
causal relationship is missing
An adverse event is considered to be “expected” if it is one where the nature or intensity is 
consistent with the information in the neridronic acid investigator’s brochure. Otherwise it is 
considered to be an “unexpected” adverse event.
15.1.1
Adverse event summaries
The following overview tables will be generated by treatment group and overall and by trial phases 
as defined above. 
1.
Summary of the number and percentage of subjects with at least 1
•
TEAE.
•
Serious TEAE.
•
Non-serious TEAE.
•
Unexpected TEAE.
•
Related TEAE.
•
Related serious TEAE.
•
TEAE leading to discontinuation from IMP.
•
TEAE leading to discontinuation from the trial.
•
Death.
The percentage denominator will be the number of subjects. 
2.
Summary of the number and percentage of TEAEs for:
•
TEAEs.
•
Serious TEAEs.
•
Non-serious TEAEs.
•
Unexpected TEAEs.
•
Related TEAEs.
•
Related serious TEAEs.
•
TEAE leading to discontinuation from IMP.
•
TEAE leading to discontinuation from the trial.
•
Death.
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The percentage denominator will be the total number of TEAEs. 
15.1.2
Incidence, incidence rates and number of events
The incidence of an adverse event is defined as the number of subjects with occurrence of this 
adverse event during the period of interest.
The incidence rate (crude incidence rate [CIR]) of an adverse event is defined as the number of 
subjects with occurrence of this adverse event during the period of interest divided by the total 
number of subjects N in the respective group (e.g., treatment group). 
The incidence, incidence rate, the number of events, and the percentage of events will be 
summarized by PT (sorted by decreasing incidence rate in the neridronic acid treatment arm for:
•
TEAEs.
•
Serious TEAEs.
•
Non-serious TEAEs.
•
Related TEAEs.
•
TEAEs associated with acute phase reactions.
Percentages will be calculated related to the total number of subjects/events presented in the 
respective table e.g., for the presentation of PTs for serious TEAEs percentages will be related to 
the number of subjects with serious TEAE/the total number of serious TEAEs, respectively.
Adverse events associated with acute phase reaction include the PT Acute Phase Reaction in all 
cases. They also include the PTs Arthralgia, Bone Pain, Chills, Fatigue, Headache, Influenza-Like 
Illness, Musculoskeletal Chest Pain, Musculoskeletal Pain, Myalgia, Pain, Pain In Extremity and 
Pyrexia, but only if occurring in the first 3 days after 1st IMP intake and not lasting longer than 3 
days.
For serious TEAEs, percentages will additionally be presented related to the total number of all 
subjects/events, respectively.
The incidence, incidence rate, the number of events and the percentage of events will be 
summarized by SOC and PT (sorted alphabetically) for each:
•
TEAEs.
•
TEAEs with an incidence rate of at least 5% (≥ 5%) in any of the treatment groups.
•
Serious TEAEs
−
Serious related TEAEs.
−
Serious fatal TEAEs.
−
Serious fatal related TEAEs.
•
Non-serious TEAEs.
•
Related TEAEs.
Percentages will be calculated related to the total number of subjects/events presented in the 
respective table e.g., for the presentation of SOC and PT for serious TEAEs percentages will be 
related to the number of subjects with serious TEAE/the total number of serious TEAEs, 
respectively.
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For serious TEAEs, percentages will additionally be presented related to the total number of all 
subjects/events, respectively.
For all enrolled subjects, the incidence, incidence rate, the number of events and the percentage of 
events (related to the total number of events) will be summarized by SOC and PT (sorted 
alphabetically) for each:
•
Pre-treatment non-TEAEs.
•
Serious pre-treatment non-TEAEs.
Presentation will only be overall and not per treatment.
The number and percentage of events will be summarized by SOC and PT (sorted alphabetically) 
for the following TEAE descriptors:
•
Intensity: mild, moderate, severe.
•
Causal relationship to the IMP: related (with sub-categories: possible, probable/likely, 
certain), not related (with sub-categories: not related, unlikely), unknown (with sub-
categories: conditional/unclassified, unassessable/unclassifiable, causal relationship 
missing).
•
Outcome: recovered/resolved, recovering/resolving, not recovered/not resolved, 
recovered/resolved with sequelae, fatal, unknown.
•
Non-IMP related countermeasures: none, newly started medication, trial discontinuation, 
others.
•
Action taken with IMP: drug interrupted, drug withdrawn, dose not changed, not 
applicable, unknown.
Denominator for percentage calculation will be the number of all TEAEs for presentation of overall 
SOCs, and the number of TEAEs per SOC or PT respectively, for the presentation per SOC or PT, 
respectively.
Measures of location and variation will be calculated for:
•
Duration of TEAEs. 
•
Time to onset of TEAE (days). 
In addition, the time to onset of TEAEs will be summarized using time-to-event methods for the
overall 5 most frequent TEAEs. Time will be weeks, until onset.
The following listings will be produced for all enrolled subjects: 
•
Deaths.
•
Serious adverse events other than death.
•
Adverse events leading to discontinuation from the trial.
•
Adverse events leading to discontinuation from IMP.
•
Adverse events leading to IMP dose decrease or interruption of IMP.
•
Adverse events associated with the acute phase reaction.
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15.2
Laboratory parameters, vital signs and ECG parameters
This section defines the general principles for the analysis of categorical and continuous parameters, 
unless specified otherwise. In general, the analysis of all parameters will be done by visit and by 
treatment group.
Categorical parameters will be descriptively summarized per visit and overall post-baseline. For an 
overall post-baseline analysis, the worst value during the on-treatment period, including 
unscheduled visits, will be derived.
If applicable, the number of not exact values will be displayed in the respective table. Continuous 
parameters will be descriptively summarized. Changes from baseline will be presented for all post-
baseline visits. Baseline values are defined as described in Section 8.2.2.
Where applicable, continuous parameters laboratory, vital signs, ECG parameter will be classified 
as low, normal, or high based on reference ranges and for parameters where sponsor alert ranges are 
defined as alert low, non-alert, or alert high (for laboratory parameters alert ranges are transferred 
with the data, for vital signs and ECG see Section 19.3). For an overall post-baseline analysis, 
values during the on-treatment period, including unscheduled visits, will be considered. If a subject 
has parameter values flagged as low and values flagged as high, the parameter will be classified as 
low+high, alert low + alert high , respectively. 
A summary of the number and the percentage of subjects with values flagged as alert low, non-
alert, alert high with respect to alert ranges will be provided for each continuous parameter.
Shift tables from baseline for the different visits and overall post-baseline will be generated for each 
continuous parameter flagged as low, normal, or high with respect to reference ranges. Denominator 
for the percentage calculation within each baseline category (low, normal, or high) will be the 
number of subjects at the respective visits.
Graphical presentations of the time course of specific continuous parameters and corresponding 
changes from baseline will be provided (mean and 95% confidence interval). At each visit, the plots 
will show the total number of subjects by treatment. On the bottom, the number of subjects flagged 
as low, and on the top the number of subjects flagged as high based on reference ranges (and alert 
low or alert high based on alert ranges), will be shown by treatment.
Shift plots by visit will be provided for specific continuous parameters with reference ranges and 
sponsor-defined alert ranges marked by vertical and horizontal lines}.
A listing of subjects with values outside the sponsor-defined alert ranges will be provided.
All parameter values will be presented in a subject data listing including respective flagging with 
respect to reference ranges and to sponsor-defined alert ranges.
Unscheduled measurements of parameters will be presented in the subject data listing. In general, 
unscheduled measurements will not be included in the analysis. However, they will be taken into 
account in the calculation of the overall post-baseline classification of parameters.
15.2.1
Laboratory parameters
Continuous and categorical laboratory parameters will be analyzed as described in Section 15.2
with individual specifications outlined in Table 2. The display of continuous laboratory parameters 
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will be by parameter group (clinical chemistry, clotting, hematology, and urinalysis). Categorical 
urinalysis parameters will be additionally classified as normal or abnormal.
Central laboratory parameters will be analyzed as described in the following paragraphs. No 
statistical analysis of local laboratory assessments, pregnancy tests, and drugs of abuse tests will be 
done. In general, all central laboratory parameters will be reported using Système International 
d’Unités (SI) units. Selected parameters will additionally be reported using US conventional units to 
facilitate safety data review (Section 19.4). The corresponding analyses of these parameters will be 
repeated using values in US conventional units.
Subjects potentially qualifying for Hy´s law criteria (FDA 2009), i.e., subjects showing post-
baseline abnormal hepatic values, will be presented in a separate listing. Subjects fulfilling the 
following 2 criteria potentially qualify for Hy’s law:
•
ALT > 3x ULN or AST >3x ULN.
•
Total bilirubin > 2x ULN.
Table 2:
Analysis of laboratory parameters
Parameter 
group
Parameter
Table of 
descriptive 
statistics
Frequency 
table 
(low/high)
Shift 
table
Mean plot
Shift plot
Clinical 
chemistry 
parameters 
(continuous)
Albumin
X
X
X
Alkaline phosphatase
X
X
X
X
X
ALT
X
X
X
AST
X
X
X
Bilirubin
X
X
X
Calcium (albumin-
corrected
X
X
X
X
X
Creatine phosphokinase
X
X
X
Creatinine
X
X
X
X
X
Estimated GFR
X
X
X
GGT
X
X
X
Glucose
X
X
X
LDH
X
X
X
Magnesium
X
X
X
Parathyroid hormone
X
X
X
Phosphate
X
X
X
Potassium
X
X
X
Protein
X
X
X
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Parameter 
group
Parameter
Table of 
descriptive 
statistics
Frequency 
table 
(low/high)
Shift 
table
Mean plot
Shift plot
Sodium
X
X
X
Tricylglycerol lipase
X
X
X
Urea
X
X
X
Uric acid
X
X
X
Vitamin D
X
X
X
Hematology 
parameters 
(continuous)
Hematocrit
X
X
X
Hemoglobin
X
X
X
Platelet count
X
X
X
RBC
X
X
X
WBC
X
X
X
Urinalysis 
parameters 
(continuous)
pH
X
X
X
Albumin (microalbumin)
X
X
X
Creatinine
X
X
X
Urinary 
albumin/creatinine ratio
(semi-quantitive dipstick)
X
X
X
Calculated urinary 
albumin/creatinine ratio 
(central laboratory)
X
X
X
Urinalysis 
parameters 
(categorical)
Bilirubin
X
X
Blood
X
X
Glucose
X
X
Ketone
X
X
Leukocytes
X
X
Nitrite
X
X
Protein
X
X
Urobilinogen
X
X
ALT = alanine transaminase; AST = aspartate transaminase; GGT = gamma-glutamyltransferase; INR = international 
normalized ratio; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular value; RBC = red blood cell; WBC = white blood cell. 
Graphical presentations over time and respective shift plots will be done for the following
continuous laboratory parameters:
•
Alkaline phosphatase.
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•
Calcium (measured).
•
Creatinine (serum).
•
Estimated glomerular filtration rate (eGFR).
•
Quantitative urinary albumin/creatinine (central laboratory value).
Urine samples potentially obtained from women of child-bearing potential will be tested locally 
using a urine ß-human chorionic gonadotropin (ß-HCG) pregnancy dipstick test. The results will be 
presented in a subject data listing.
Urine samples will be obtained from all subjects at the Enrollment Visit for testing for drugs of 
abuse. The drugs to be screened for using suitable validated methods (e.g., dipstick) include: 
cocaine, 3,4-methylendioxy methamphetamine, ecstasy (MDMA), amphetamines, cannabinoids. 
The results will be presented in a subject data listing.
15.2.2
Vital signs
Descriptive statistics for the vital signs parameters (systolic and diastolic blood pressure, pulse rate, 
weight, body mass index BMI [kg/m²]) will be analyzed as described in Section 15.2. 
Frequency tables and shift tables with respect to sponsor-defined alert ranges as described in 
Section 15.2 will be created.
15.2.3
Electrocardiogram
Descriptive statistics for the electrocardiogram (ECG) parameters (continuous) heart rate, PR 
interval, QT interval, QTcF interval, RR interval will be analyzed as described in Section 15.2.
The ECG printouts will be interpreted by the investigator as “normal”, “abnormal, but clinically not 
relevant”, or “abnormal and clinically relevant”. Results from this interpretation will be reported in 
subject data listings. Moreover, the results from the ECG interpretation will be descriptively 
summarized.
In addition, a subject data listing of all abnormal, clinically relevant findings as documented by the 
investigator in the e-CRF will be created.
15.3
Physical examination
A general physical examination will be done at the Enrollment Visit (Visit 1) by rating each body 
system as normal or abnormal. At all subsequent visits, including unscheduled visits, updates of the 
physical status since the previous visit are recorded by rating the body system as unchanged or 
changed.
The results will be presented in a subject data listing.
16
INTERIM ANALYSIS
16.1
Interim analysis of efficacy
The interim analysis will be further described in a separate SAP as it will be performed on the 
pooled data of two trials.
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17
REFERENCES
Armitage P, Berry G, Matthews JNS. Analysing means and proportions. In: Statistical methods in 
medical research. 4th ed. Blackwell Science, USA: Malden 2002, p.127.
Association for Applied Human Pharmacology (AGAH) Working Group Pharmacokinetics: 
Collection of terms, symbols, equations, and explanations of common pharmacokinetic and 
pharmacodynamic parameters and some statistical functions. Version 16 February 2004.
Cella D, Yount S, Rothrock N, Gershon R, Cook K, Reeve B, et al. The Patient-Reported Outcomes 
Measurement Information System (PROMIS): progress of an NIH Roadmap Cooperative Group 
during its first two years. Med Care 2007; 45 (5): S3-11.
Carpenter JR, Kenward MG. Choosing the number of imputations. In: Multiple Imputation and its 
Application. New York: Wiley; 2013. pp. 54-5.
Clinical Data Interchange Standards Consortium (CDISC) Submission Data Standards Team. Study 
Data Tabulation Model Implementation Guide: Human Clinical Trials. Version 3.2, 2013.
Dmitrienko A, D’Agostino R Sr. Traditional multiplicity adjustment methods in clinical trials. Stat 
Med 2013; 32 (29): 5172-218.
Gauthier, LR, Young A, Dworkin RH, Rodin G, Zimmermann C, Warr D, et al. Validation of the 
short-form McgGill pain questionnaire-2 in younger and older people with cancer pain. J Pain 2014;
15 (7): 756-70.
Gou J, Tamhane, Xi D, Rom D. A class of improved hybrid Hochberg-Hommel type step-up 
multiple test procedures. Biometrika 2014; 101 (4): 899-911.
Harden RN, Bruehl S, Perez RS, Birklein F, Marinus J, Maihofner C, et al. Development of a 
severity score for CRPS. Pain 2010b; 151 (3): 870-6.
Harden RN, Bruehl S, Perez SG, Birklein F, Marinus J, Maihofner C, et al. Validation of proposed 
diagnostic criteria (the “Budapest Criteria”) for Complex Regional Pain Syndrome. Pain 2010a; 
150 (2): 268-74.
Harden RN, Oaklander AL, Burton AW, Perez RS, Richardson K, Swan M, et al. Complex regional 
pain syndrome: practical diagnostic and treatment guidelines, 4th Edition. Pain Med 2013; 14 (2): 
180-229.
Little RJ, Rubin DB. Estimation of imputation uncertainty. In: Statistical analysis with missing data.
2nd ed. New York: Wiley; 2002. pp. 75-91. 
Maier C, Baron R, Tölle TR, Binder A, Birbaumer N, Birklein F, et al. Quantitative sensory testing 
in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 
1236 patients with different neuropathic pain syndromes. Pain 2010; 150 (3): 439-50.
Mainka T, Bischoff FS, Baron R, Krumova EK, Nicolas V, Pennekamp W, et al. Comparison of 
muscle and joint pressure-pain thresholds in patients with complex regional pain syndrome and 
upper limb pain of other origin. Pain 2014; 155 (3): 591-7.
Mallinckrodt CH, Lane PW, Schnell D, Peng Y, Mancuso JP. Recommendations for the primary 
analysis of continuous endpoints in longitudinal clinical trials. Drug Inf J 2008; 42 (4): 303-19.
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Nicholas MK. The pain self-efficacy questionnaire: Taking pain into account. Eur J Pain 2007; 11
(2): 153-63.
Pilkonis PA, Choi SW, Reise SP, Stover AM, Riley WT, Cella D on behalf of the PROMIS 
Cooperative Group. Item banks for measuring emotional distress from the Patient-Reported 
Outcomes Measurement Information System (PROMIS®): depression, anxiety, and anger. 
Assessment 2011; 18 (3): 263-83.
PROMIS Adult profile Instruments 2015 
https://www.assessmentcenter.net/documents/PROMIS%20Profile%20Scoring%20Manual.pdfhttps
://www.assessmentcenter.net/documents/PROMIS%20Profile%20Scoring%20Manual.pdf - last 
accessed on 08 May 2018.
Rolke R, Andrews K., Magerl W, Treede R-D. Investigator’s Brochure. A standardized battery of 
Quantitative Sensory Testing according to the protocol of the German Research Network on 
Neuropathic Pain (DFNS), v2.1, 2010. Accessed at http://www.neuro.med.tumuenchen. 
de/dfns/pdfs/QST-Investigators_brochure_Version_2_1_final_english_2010_07_09.pdf.
Sullivan MJL. The Pain Catastrophizing Scale – User Manual (2009).
Verbeke G, Molenberghs G. Joint modeling of measurements and missingness. In: Linear mixed 
models for longitudinal data. Springer Series in Statistics; 2009. pp. 209-19. 
18
CHANGES TO THE SAP
18.1
Amendments
Not applicable.
19
APPENDIX
19.1
Data derivation and analysis rules
The purpose of this section is to give technical details for the implementation of the SAP. 
19.1.1
General specifications
19.1.1.1
Percentages and decimal places
If not otherwise specified, the following rules are applied:
•
Percentages are presented to 1 decimal point. 
•
Percentages equal to 0 or 100 are presented as such without a decimal point. 
•
For descriptive summary statistics, the same number of decimal places as in the raw data 
are presented when reporting minimum and maximum values, 1 more decimal place when 
reporting mean, median, quartiles and confidence interval and standard deviation.
•
P-values are presented to 3 decimal points. P-values <0.001 will be reported as such.
•
Ratios are presented to 3 decimal points.
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The above described displaying rules must not be changed (e.g., rounding) for the integrated 
clinical trial report text and are used 1:1 in the body report as well. For analysis of pharmacokinetic
data, see also Section 19.1.5.
19.1.1.2
Presentation of descriptive statistics
Calculation of mean: if not otherwise specified (e.g., for pharmacokinetic data), the arithmetic mean 
is used.
Table 3:
Presentation of descriptive statistics in clinical trials
Number of non-
missing values
n
Missing n
Mean
SD
Min
Q1
Median
Q3
Max
0
+
+
-
-
-
-
-
-
-
1.2.3.4
+
+
+
-
+
-
+
-
+
≥5
+
+
+
+
+
+
+
+
+
+ summary statistic will be presented; - summary statistic will not be presented.
CI = confidence interval, Max = maximum, Min = minimum, n = number of values, Q1 = first quartile, Q3 = third 
quartile, SD = standard deviation
19.1.1.3
Presentation of differences and changes
For differences between active comparator and placebo, the active comparator will constitute the 
minuend and placebo the subtrahend. 
For changes from baseline, the baseline value will constitute the subtrahend and the later value the 
minuend. 
19.1.1.4
Trial day count
The day of baseline visit (Visit 2) is defined as trial Day 1.
Calculate the trial day according to the following rules:
•
If date < trial Day 1, then trial day = Date – trial Day 1.
•
If date > trial Day 1, then trial day = Date – trial Day 1 +1.
19.1.1.5
Presentation of units
If applicable, parameters will be displayed together with the used unit of measurement. The unit of 
measurement is enclosed in square brackets ([ ]).
19.1.1.6
Presentation of dates
Where applicable (e.g., in listings), dates will be displayed in ISO8601 format (example: 2014-09-
29T12:16, see CDISC 2013). In case of incomplete dates, both the original value and the imputed 
value is displayed.
19.1.1.7
Handling of missing values
At each time point/visit, all subjects still in the trial are reported. This is defined as all subjects that 
have not discontinued the trial before the respective visit and are identified by a visit date. Missing 
values will be taken into account as missing in the analysis. The number of observed values and the 
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number of missing values must add up to the number of subjects in the trial at the respective time 
point/visit.
Unless otherwise specified in the SAP, missing values will not be imputed. If missing values are 
imputed, the result of all imputation strategies and newly derived information must be stored in the 
ADaM data set. The shifts required for the shift tables should already be included in the ADaM data 
set.
Imputed values will be listed in the subject data listing and marked as imputed.
19.1.1.8
Visit windows
Since all assessments not done in the eDiary assessments are linked to specific visits no visit 
windows definition is needed are needed. Nevertheless if values or changes from baseline to a 
specific week are to be displayed the respective visit value is to be used. E.g. for responder analysis 
based on the tablet computer described in Section 13.2.2 the average pain intensity Week 26 is 
needed, which in fact related to the value documented for Visit 11. 
19.1.1.9
Handling of data from early termination visits
Subjects who discontinue the 52-week trial period before their Week 52 visit (Visit 17) are 
requested to undergo an Early Termination Visit with identical procedures to Visit 17. Data from 
the Early Termination Visit recorded under Visit 17 will not be included in the analysis of data from 
scheduled visits at Visit 17. 
Instead data from the Early Termination Visit will be assigned to the nearest scheduled visit based 
on the study day of the early termination visit and the planned visit day. The planned visit day is 
•
Day 1 for Visit 2
•
Day 4 for Visit 3
•
Day 7 for Visit 4
•
Day 10 for Visit 5
•
Day 15 for Visit 6
•
Day 43 for Visit 7
•
Day 85 for Visit 8
•
Day 113 for Visit 9
•
Day 155 for Visit 10
•
Day 183 for Visit 11
•
Day 186 for Visit 12 (only if subject is retreated)
•
Day 189 for Visit 13 (only if subject is retreated)
•
Day 192 for Visit 14 (only if subject is retreated)
•
Day 197 for Visit 15 (only if subject is retreated)
•
Day 253 for Visit 16
•
Day 365 for Visit 17
In case of equal distance to two scheduled visits the earlier visit will be chosen. If the assigned visit 
already occurred before the early termination visit, then the data will be assigned to the next 
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scheduled visit. Visits 12, 13, 14 and 15 are only applicable for subjects who have been treated in 
Treatment Period B.
Data from the Early Termination Visit will be analyzed using the re-assigned visits.
19.1.1.10
Assessments of on-treatment-period
For the calculation of the on-treatment-period the date information given for IMP administration
will be used as documented in the e-CRF and according to the definition in Section 8.2.2.
19.1.1.11
Conversion of time intervals
If a time interval was calculated in minutes, hours or days and needs to be converted into months or 
years, the following conversion factors will be used:
•
1 month = 30 days.
•
1 year = 365.25 days.
19.1.1.12
End of treatment 
End of treatment is the date of last administration of IMP given on the End-of-trial page in e-CRF. 
19.1.1.13
Mandatory tables without data
Recommended tables must be created. If no subject qualifies for the table, the header will be created
and the table itself will be replaced by “No subject in this category”.
19.1.1.14
Kaplan-Meier analysis
For Kaplan-Meier analyses in the 12-week trial period, the unit of time is days, the start time is the 
date/time of first IMP, and the censoring time is the day of Visit 8 or, in case of dropouts, the day of 
the Early discontinuation Visit 17. 
19.1.2
Disposition
There are no trial-specific definitions for this trial.
19.1.2.1
Subject discontinuation
Reasons for subject discontinuation as specified in the End-of-trial page or reason for permanent 
discontinuation of IMP from the respective Treatment Period A/B completer page of the e-CRF will 
be used. 
19.1.2.2
Protocol deviations
Protocol deviations are based on the analysis dataset ADDV. Major protocol deviations are 
retrieved from the respective SDTM dataset (SDTM.DV.DVCAT). No further protocol deviations 
are programmed in the analysis datasets for ADDV (if not otherwise specified in the SAP).
19.1.3
Demographics and other baseline characteristics
19.1.3.1
Subject demographics
Derivation of age
Age as derived in SDTM.DM.AGE will be used
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Derivation of BMI:
BMI is extracted from the SDTM.
Derivation of race:
If for race more than 1 entry per subject is documented, a category “multiple” will be created.
19.1.3.2
CRPS history
For CRPS history, time since inciting or precipitating event (months), time since onset of CRPS 
symptoms (months), time since diagnosis of CRPS (months) are derived. 
If the corresponding date reported in the eCRF is incomplete, e.g., missing day or month (year is 
mandatory), then the missing day or month will be imputed. Missing dates will be imputed 
conservatively, i.e., missing values will be imputed in such a way that the imputed date leads the 
longest possible time since event. Missing months will be imputed by the first calendar month of 
the year, and missing days will be imputed by the first calendar day of the (imputed) month.
Missing date
Imputed date
2018-Mar
2018-Mar-01
2018
2018-Jan-01
19.1.3.3
Prior and concomitant medication or therapy
Prior and concomitant medication is collected as of enrollment in the e-CRF and described like that 
in the trial protocol. For the analysis, the definition as described in the following is used.
The following rules are used to define the categories “prior” and “concomitant” medication.
Pre-requisite is a complete date of first dose of IMP (entered or imputed).
Stop of medication
Date
Condition
Category
Complete date is available
Stop date is earlier than date of first dose of IMP.
Prior
Missing month
Year of stop date is earlier than year of first dose of IMP.
Prior
Missing day
Month/year of stop date are earlier than month/year of first dose of 
IMP.
Prior
Otherwise
Concomitant
Medication ticked in the e-CRF as “continuing” will be classified as concomitant.
For time to first concomitant analgesic medication start dates might need to be imputed. Imputation 
will be done as for CRPS history but if imputed date would be before first IMP date of first IMP 
will be used.
19.1.4
Efficacy analysis
Not applicable.
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19.1.5
Analysis of pharmacokinetic and pharmacodynamic parameters
Pharmacokinetic values (concentrations and concentration related parameters) including their 
descriptive statistics will be shown using 3 significant digits e.g., 123 or 12.3 or 0.123. Values 
above 1000 will be presented as integers. Statistical calculations will be performed with values that 
have not been rounded. 
The coefficient of variation (CV) will be presented as percentage with 1 decimal. 
A missing pre-dose value in single-dose trials will be replaced by 0.
The time axis of the plots should be broken after the first day and before the last one using different 
scales for the different kind of profiles (e.g., the 0-24 h time period on the first and the last day 
should have approximately the same width as the remaining part with the trough values).
Derivation of geometric mean and geometric coefficient of variation
Geometric mean=exp(arithmetic mean of log-transformed values)
Zeros will be excluded from the calculation of the geometric mean.
Geometric. CV%= (sqrt (exp (variance for log transformed data)-1)) *100
19.1.6
Safety analysis
19.1.6.1
Adverse events
The result of all imputation strategies (e.g., incomplete start dates of adverse events), combination 
of observations and new derived information (e.g., treatment-emergent flag) must be stored in 
ADaM data set.
Handling of missing date information
The term missing date/time refers to a completely missing date /time or to an incomplete date/time 
where parts are not available e.g., missing hours. 
The following imputation strategy is applied. 
If the number of adverse events with missing date/time information exceeds 10%, the imputation 
strategy is only applied to assess if an adverse event is a TEAE but not for any other calculation 
(e.g., duration, onset). 
Missing start and end date/times will be imputed conservatively, i.e., missing values will be 
imputed in such a way that the duration of the adverse event is considered with the longest possible 
duration and such that, whenever the adverse event may potentially start after first IMP 
administration, the adverse event will be handled as a TEAE.
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I1-I4: imputation steps
C1-C4: checkpoints
AE = adverse event, IMP = investigational medicinal product
Figure 1:
Graphical overview about the imputation strategy
Further explanations on the flow chart:
The different steps of the displayed imputation strategy must be completed from the first to the last 
step. All procedures in each step must be completed in the order given.
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•
Imputation:
−
I1: Impute with date/time of first IMP
{If administration of IMP was not collected with time information set adverse event
start time to 00:00.}
−
I2:
a) Impute with first calendar day and/or first calendar month
Imputation will be done based on the available partial information starting with month 
and then day. The respective first month and day will be chosen for imputation:
Missing date
Imputed date
2014-Mar
2014-Mar-01
2014
2014-Jan-01
b) Impute with first hour and/or first minute
Imputation will be done based on the available partial information starting with hour 
and then minutes. The respective first hour of a day and first minute will be chosen for 
imputation. “00:00” will be considered as the first hour/first minute per day. 
Missing time
Imputed time
11:--
11:00
--:--
00:00
}
−
I3: Impute with date/time of informed consent signed 
If signing of informed consent was not collected with time information, set the adverse 
event start time to 00:00.
−
I4:
a) Impute with last calendar day and/or calendar last month
Imputation will be done based on the available partial information starting with month 
and then day. The respective last month and day will be chosen for imputation:
Missing date
Imputed data
2014-Mar
2014-Mar-31
2014
2014-Dec-31
For February leap years must to be taken into account when calculating the last day in February.
1.1. b: Impute with last hour and/or last minute
Imputation will be done based on the available partial information starting with hour and 
then minutes. The respective last hour of a day and last minute will be chosen for 
imputation. “23:59” will be considered as the last hour/last minute per day.
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Missing time
Imputed time
11:--
11:59
--:--
23:59
•
Checkpoints
−
C1: The decision must be taken based on the available information (date /time) before 
imputation. 
−
C2: Adverse event stop date before first IMP
1.2. 1) The decision must be taken based on the available information (date/time) before 
imputation.
2) If the end date is completely missing (with or without the information that the adverse 
event was continuing), this will be considered as after first IMP.
3) If no IMP was given, this will be treated as adverse event stop date before the first IMP.
−
C3: The decision must be taken based on the available information (date/time) before 
imputation.
−
C4: The decision must be taken based on the available information (date/time) before 
imputation.
A replacement of missing year for adverse event start information is not foreseen. If needed, this 
will be considered on a case-by-case decision which must be documented together with the 
documentation of ADaM data sets.
Assessment of TEAEs
The assessment whether an adverse event is a TEAE will be done after replacement of missing 
date/time information. 
Assignment adverse events to time periods/trial phases
Assignment of adverse events to time periods/trial phases will be done after replacement of missing 
date/time information. 
List of deaths
Death will be identified by outcome of adverse event equals “fatal”. 
Please also check all PTs for “death”.
Treatment emergent adverse events leading to discontinuation from IMP or leading to 
discontinuation from trial
Treatment emergent adverse events leading to discontinuation from IMP will be identified as 
treatment emergent adverse events with “Action taken with IMP” being “Drug withdrawn”.
Treatment emergent adverse events leading to discontinuation from trial will be identified as 
treatment emergent adverse events with “Countermeasure” being “Trial discontinuation”.
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Time to onset of adverse events
Time to onset of adverse events will be calculated based on the first administration of IMP based on 
the imputed value for adverse event start date/time. 
Duration of adverse events
Duration of adverse event will be calculated based on the imputed values for adverse event start 
date/time and stop date/time. 
If the duration of the adverse event could not be calculated due to unknown date information, the 
following assessment to categories will be used:
•
If the adverse event is marked as “continuing” in the {e-}CRF, the duration will be 
categorized as “continuing”.
•
Otherwise, the duration category will be set to “missing”.
Subject experiencing a non-serious treatment emergent adverse event
All subjects who had at least 1 non-serious TEAE will be taken into account regardless of the 
experience of a serious TEAE. 
19.1.6.2
Laboratory parameters, vital signs and ECG parameters
For categorical parameters, 2 types of tables are created:
1.
Frequency tables display the pre-defined categories by time point/visit and overall post-
baseline.
2.
Shift tables display the shift from baseline at each time point/visit and overall.
Both types of tables show the number of subjects still in the trial (n) at the time point/visit and the 
number of missing values (nMiss) at the time point/visit. For the overall presentation, all post-
baseline values on treatment are taken into account and nMiss is the number of subjects without any 
on-treatment post-baseline values. 
For all ordinary levels of the categorical parameter including missing values, both the number and 
the corresponding percentage is displayed. If no missing values occur at any time point/visit, then 
the number of missing values can be omitted. 
For descriptive statistics of continuous parameters, n is the number of subjects with recorded values 
and nMiss is the number of missing values at the respective time point/visit. The analysis of 
changes from baseline (e.g., baseline versus End of treatment) is based on subjects with non-
missing values at both visits; for all other subjects, the change is missing.
Unscheduled visits
Unscheduled visits are time points not planned in the protocol.
In listings, unscheduled visits will be listed as recorded. All visits will be ordered chronologically 
including the dates of unscheduled visits.
Unscheduled visits will be incorporated in the overall post-baseline summary in tables. If the date is 
incomplete, but it can be determined whether values were measured in the on-treatment period, they 
will be incorporated in overall post-baseline summaries. Unscheduled visits will be excluded from 
the per time point/visit presentation.
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Not exact values 
Not exact laboratory values such as < x, > x will not be included in the analysis of continuous 
parameters. The frequency of occurrence of not exact values will be displayed in the respective 
table where applicable. 
Handling of not exact values in a categorical analysis is described in the section below (“Values out 
of range”).
Values out of range
For presentation of laboratory values as out of normal/sponsor-defined alert ranges, the flags as 
created by the laboratory are used.
In tables where parameters are classified as abnormal low, normal, abnormal high based on 
reference ranges and alert low, normal, alert high based on sponsor-defined alert ranges as defined 
in SDTM datasets or Section 19.3, the available pre-defined categories must be displayed in tables 
even if there are categories to which no subjects belong. Categories that are not applicable must be 
omitted (e.g., HDL abnormal high). 
For the overall post-baseline summary (including all on-treatment post-BL time points/visits), 
subjects might have both low and high values. These subjects will be categorized in a new category 
“high and low” and excluded from the categories “high” and “low”. The inclusion of this category 
in the frequency and shift tables is only required if there are any subjects falling into this category.
Ordering of parameters
Laboratory parameters, vital signs and ECG parameters will be ordered alphabetically within their 
parameter group (e.g., hematology, clinical chemistry, and urinalysis). Time points/visits will be 
sorted chronologically. If changes from baseline are displayed by time point/visit, all visits will be 
displayed first followed by all the changes from baseline.
19.2
List of statistical output documentation
The statistical output documentation will contain the original SAS-output for the analyses (incl. 
sensitivity analysis) of the primary and the secondary endpoint. No subject numbers are to be 
display, and hence subject number output will be suppressed.
19.3
Reference ranges and alert ranges
Vital signs and ECG parameters will be flagged as low or high based on reference ranges and 
sponsor-defined alert ranges, respectively. This section defines the reference and alert ranges for 
vital signs, and the alert ranges for ECG parameters. No reference ranges are defined for ECG 
parameters.
19.3.1
Reference ranges for vital signs
The reference ranges for vital signs are defined in Table 4.
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Table 4: 
Reference ranges for vital signs parameters
Panel
Parameter
LLN
ULN
Vital signs 
Blood pressure (diastolic)
< 50 mmHg
> 90 mmHg
Blood pressure (systolic)
< 90 mmHg
> 140 mmHg
Pulse rate
< 60 bpm
> 100 bpm
Respiratory rate
< 10 breaths/min
> 20 breaths/min
bpm – beats per minute. mmHg – millimeter of mercury. LLN – lower limit of normal. ULN – upper limit of normal.
19.3.2
Sponsor-defined alert ranges for vital signs
The following table defines the sponsor-defined alert ranges for those vital signs parameters where 
lower or upper limits are specified.
Table 5: 
Sponsor-defined alert ranges for vital signs parameters
Panel
Parameter
Alert low
Alert high
Vital signs 
Blood pressure (diastolic)
-
> 110 mmHg
Blood pressure (systolic)
< 80 mmHg
> 180 mmHg
Pulse rate
< 45 bpm
> 120 bpm
bpm – beats per minute. mmHg – millimeter of mercury.
19.3.3
Sponsor-defined alert ranges for ECG parameters
The following table defines the sponsor-defined alert ranges for those ECG parameters where lower 
or upper limits are specified.
Table 6: 
Sponsor-defined alert ranges for ECG parameters
Panel
Parameter
Alert low
Alert high
ECG 
Heart rate
< 45 bpm
> 120 bpm
PR interval
-
> 270 msec
QT interval
-
> 500 msec
QTcF interval
<300 msec
> 480 msec
bpm – beats per minute. msec – milliseconds.
19.4
Laboratory parameters reported in US conventional units
Selected laboratory parameters will additionally be reported using US conventional units. The 
following table lists the selected parameters.
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Table 7:
Laboratory parameters reported in US conventional units
Lab panel
Parameter
Clinical chemistry panel 
(continuous)
Albumin
Blood urea nitrogen (BUN)
Calcium (albumin-corrected)
Calcium (measured)
Cholesterol
Creatinine (serum)
Glucose
Magnesium
Parathyroid hormone a
Phosphorus
Total bilirubin
Total protein
Triglycerides
Uric acid
Vitamin D
Hematology panel (continuous)
Hematocrit
Hemoglobin
Urinalysis panel (continuous)
Urinary ACR
Urinary creatinine
a) Enrollment Visit only.
ACR = albumin creatinine ratio; LDH = lactic acid dehydrogenase; MCHC = mean cell hemoglobin concentration.
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SDR-PRO-TEMPLATE-02
CONFIDENTIAL
The contents of this document may not be disclosed to any other person without written permission from the sponsor, 
unless required by good clinical practice or applicable regulatory requirements. Any supplemental documentation for 
the clinical trial is also covered by this provision.
Trial code:
KF7013-02
Title of trial:
Randomized, double-blind, placebo-controlled trial investigating the 
efficacy and safety of intravenous neridronic acid in subjects with 
complex regional pain syndrome (CRPS)
Brief title:
Efficacy and safety of intravenous neridronic acid in CRPS
Indication:
Treatment of CRPS
International 
coordinating
investigator a:
Prof Dr 
Neurologische Klinik und Poliklinik, Universitätsklinikum Würzburg, 
Josef-Schneider-Str. 11, 97080, Würzburg, Germany
Telephone: +49 (0) 931-201-
Trial sites:
Multi-site trial (approximately 80 sites in the United States, European 
Union, and other regions).
Documentation of the involved trial sites will be maintained.
Trial sponsor:
Grünenthal GmbH, 52099 Aachen, Germany
Sponsor’s medically 
qualified person a
, MD, Clinical Trial Physician
Telephone: +49 (0) 241-569-0
Sponsor’s signatory:
, MD, International Clinical Lead
Telephone: +49 (0) 241-569-0
Public contact point:
Email: clinical-trials@grunenthal.com;
Telephone: +49 (0) 241-569-3223
a) Contact detail changes during the course of the trial will be documented and do not require a protocol amendment.
Version
Date
DMS version number
Valid for
Original:
14 Mar 2018
2.0
All countries
Amendment 01
20 Nov 2018
3.0
All countries
IND number:
115811 (US sites only)
EudraCT number:
2016-003833-91
Universal Trial 
Number:
U1111-1187-8036
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a) Subjects going into Treatment Period B only.
D = Day, V = Visit, W = Week.
1.1.2
Brief description of the sequence and duration of all trial periods
There will be an Enrollment Period lasting up to 60 days, Treatment Period A consisting of 
4 infusions over 10 days, and Follow-up Period 1 from Visit 6 (Week 2) up until Visit 11
(Week 26).
At Visit 11 (Week 26), subjects not meeting the pre-specified criteria to continue into Treatment 
Period B (see Section 1.3.3) will continue in Follow-up Period 2 until Visit 17 (Week 52). Subjects 
meeting the pre-specified criteria will enter the open-label Treatment Period B with 4 additional
infusions over 10 days and follow-up visits until Visit 17 (Week 52).
Each subject is expected to be in the trial for approximately 14 months.
See Section 1.1.1 for a summary of the trial as a flow diagram and Section 1.7 for tabular schedules
of events.
1.2
Trial objectives, endpoints, and outcomes
Objective
Endpoint/Outcome
Measure description and timeframe
Primary
Primary
Primary
To demonstrate the superior 
efficacy of a cumulative dose of 
400 mg intravenous neridronic 
acid versus placebo for the 
treatment of CRPS-related pain.
Change from baseline to 
Week 12 in the average pain 
intensity score (weekly average 
of pain values recorded daily in 
the electronic diary).
11-point numerical rating scale (NRS)—from 
0 = “no pain” to 10 = “pain as bad as you can 
imagine” —reported once daily (in the 
evening, 24-hour recall) in an electronic diary.
The change from the baseline phase (Day -7 to 
Day -1) to Week 12 will be analyzed.
Secondary
Secondary
Secondary
To assess the efficacy of a 
cumulative dose of 400 mg 
intravenous neridronic acid 
versus placebo for the treatment 
of CRPS-related pain.
Change from baseline to 
Week 26 in the average pain 
intensity recorded on the tablet 
computer.
11-point NRS—from 0 = “no pain” to 
10 = “pain as bad as you can imagine”—
reported at the visits on a tablet computer (24-
hour recall). The change from baseline (Visit 2 
[Day 1]) to Visit 11 (Week 26) will be 
analyzed.
Pain response to treatment, 
defined as at least 30% decrease 
from baseline in the average 
pain intensity at Week 12, 
recorded on the tablet computer.
11-point NRS—from 0 = “no pain” to 
10 = “pain as bad as you can imagine”—
reported at the visits on a tablet computer (24-
hour recall). The change from baseline (Visit 2 
[Day 1]) to Visit 8 (Week 12) will be 
analyzed.
Pain response to treatment, 
defined as at least 30% decrease 
from baseline in the average 
pain intensity at Week 26, 
recorded on the tablet computer.
11-point NRS—from 0 = “no pain” to 
10 = “pain as bad as you can imagine”—
reported at the visits on a tablet computer (24-
hour recall). The change from baseline (Visit 2 
[Day 1]) to Visit 11 (Week 26) will be 
analyzed.
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Objective
Endpoint/Outcome
Measure description and timeframe
Secondary
Secondary
Secondary
To assess the efficacy of a 
cumulative dose of 400 mg 
intravenous neridronic acid 
versus placebo on the dynamic 
mechanical allodynia (DMA).
Change from baseline to 
Week 12 in the pain intensity 
level of DMA.
Dynamic mechanical allodynia: a tactile 
stimulus is applied in a single sweeping 
motion (1 cm to 2 cm length) on the skin on 
the affected limb.
The subjects are asked to judge the stimulus 
intensity by means of an NRS (0 to 10). “0” in 
this case means “no pain”. Each “pricking”, 
“stinging” or “burning” sensation is defined as 
a painful sensation, which should always be 
evaluated by giving a value greater than “0”. 
“10” corresponds to the individual maximum 
pain imaginable.
The change from baseline (Visit 2 [Day 1]) to 
Visit 8 (Week 12) will be analyzed.
To assess the efficacy of a 
cumulative dose of 400 mg 
intravenous neridronic acid 
versus placebo on the pressure 
pain threshold (PPT).
Change from baseline to 
Week 12 in the PPT ratio for the 
thenar muscle/abductor hallucis 
muscle.
Pressure pain threshold: using a pressure 
algometer (contact area 1 cm2), the threshold 
for pressure-induced pain is measured on the 
thenar muscle/abductor hallucis muscle in 
3 series of slowly increasing stimulus 
intensities (at a rate of about 50 kPa/s). The 
threshold is then determined as the arithmetic 
mean of the 3 series (in kPa). 
The ratio of the thresholds of the affected limb 
versus the unaffected limb will be calculated.
The change from baseline (Visit 2 [Day 1]) to 
Visit 8 (Week 12) will be analyzed.
To assess the efficacy of a 
cumulative dose of 400 mg 
intravenous neridronic acid 
versus placebo on edema of the 
hand or foot.
Change from baseline to 
Week 12 in the ratio of the 
figure of eight measurements of 
the affected limb versus the 
unaffected limb.
In subjects with the CRPS sign of edema on 
the CRPS Severity Score at baseline, 
circumference of the hand or foot will be 
measured by the investigator with 
measurement tape using the figure-of-eight 
method at both the affected limb and the 
contralateral unaffected limb. Each 
measurement will be performed 3 times. The 
average of the 3 measurements will be used 
for further analysis.
The ratio of the averages of the affected limb 
versus the unaffected limb will be calculated.
The change from baseline (Visit 2 [Day 1]) to 
Visit 8 (Week 12) will be analyzed.
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Other data to be collected that are not directly attributed to or considered as an endpoint
General note: All efficacy and safety data evaluated during Treatment Period B and Follow-up Period 2 will be 
analyzed descriptively separately for subjects who are treated in Treatment Period B and subjects who are not treated.
For subjects treated in Treatment Period B, analyses will be performed for subjects initially treated with placebo and 
subjects initially treated with neridronic acid.
All efficacy assessments will be evaluated for the time points indicated in the schedules of events.
To assess the efficacy of neridronic acid in subjects with CRPS
•
Change from baseline in average pain intensity recorded on the tablet computer.
•
Change from Week 26 in average pain intensity recorded on the tablet computer.
•
Pain response to treatment, defined as at least 50% decrease from baseline in the average pain intensity, 
based on pain intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 50% decrease from Week 26 in the average pain intensity, 
based on pain intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 30% decrease from baseline in the average pain intensity, 
based on pain intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 30% decrease from Week 26 in the average pain intensity, 
based on pain intensity recordings on the tablet computer.
•
Change from baseline in pain intensity scores determined using worst and current pain ratings recorded 
daily in the electronic diary.
•
Change from baseline in worst and current pain intensity ratings, recorded on the tablet computer.
•
Change from Week 26 in worst and current pain intensity ratings, recorded on the tablet computer.
•
Duration of effect based on average pain intensity recordings in the electronic diary.
•
Change from baseline in the pain intensity level of DMA.
•
Change from baseline in PPT ratios.
•
Change from baseline in the ratio of the figure of eight measurements of the affected limb versus the 
unaffected limb.
•
Change from baseline in the active range of motion (AROM) ratio (affected limb and unaffected limb) 
measured in the hand or foot, respectively.
•
Change from baseline in the CRPS Severity Score.
•
Patient Global Impression of Change (PGIC).
•
Patient Global Impression of Severity (PGI-S).
•
Change from baseline in the EuroQoL-5 Dimension-5 level (EQ-5D-5L) index score and the health-related 
visual analog scale (VAS) score.
•
Change from Week 26 in the EQ-5D-5L index score and the health-related VAS score.
•
Change from baseline in the responses to questions on the following questionnaires (recorded on the tablet 
computer):
−
Patient-Reported Outcomes Measurement Information System (PROMIS®)-29 profile version 2.0 
(PROMIS-29 profile) (sub-scores: physical function, anxiety, depression, fatigue, sleep disturbance, 
social roles and activities, and pain interference). The change from baseline to Week 16 and Week 22 
will be assessed for question number 29, GLOBAL07 only.
−
The 6 neuropathic pain items of the Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2) (single 
items and the combined score).
−
Pain Catastrophizing Scale (PCS).
−
Pain Self Efficacy Questionnaire (PSEQ).
−
Response to Question EDDEP39 of the PROMIS Item Bank version 1.0 – Emotional Distress –
Depression (PROMIS-EDDEP39) (recorded on the tablet computer).
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•
Concomitant analgesic medication use.
To describe the trial population and to evaluate subject eligibility
•
Demographic data, medical history, dental history, CRPS history, prior medication and therapies, beta-
human chorionic gonadotropin (ß-HCG) pregnancy test, and drugs of abuse test.
To assess the safety and tolerability of neridronic acid in subjects with CRPS
•
Adverse events, concomitant medications, physical examination findings, 12-lead electrocardiograms 
(ECGs), vital signs, body weight, and safety laboratory data.
To assess the pharmacodynamics of neridronic acid in subjects with CRPS
•
Concentrations of bone turnover markers in serum: (C-terminal telopeptide of type I collagen [CTX], bone 
alkaline phosphatase [BAP], and procollagen type I amino-terminal propeptide [PINP]).
To assess the pharmacokinetics of neridronic acid in subjects with CRPS
•
Concentrations of neridronic acid in plasma.
To assess health economics and work productivity (US sites only)
•
Work Productivity and Activity Impairment Questionnaire: CRPS (WPAI: CRPS).
•
Medical resources utilization.
To explore markers for disease severity or progression in CRPS
•
Concentrations of soluble interleukin-2 receptor (sIL-2R).
1.3
Trial subjects – the population to be studied
1.3.1
Inclusion criteria
Subjects are eligible for the trial if all the inclusion criteria apply. Subjects will only receive
investigational medicinal product (IMP) if documentation is available showing that they meet all of 
these inclusion criteria.
1.
Informed consent signed.
2.
Male or female subjects at least 18 years of age at Visit 1.
3.
A diagnosis of CRPS according to the clinical diagnostic criteria recommended by the 
International Association for the Study of Pain (IASP; “Budapest clinical criteria”), assessed at 
Visit 1. Signs and symptoms of CRPS must apply to an affected limb (arm or leg) and must 
demonstrate asymmetry with respect to the contralateral limb. The CRPS duration must be 
2 years or less since onset of symptoms.
4.
A baseline average pain intensity score of greater than or equal to 4 using an 11-point NRS, 
referring to the CRPS-affected limb (average of pain recorded over 7 days). The baseline 
average pain intensity score will be calculated automatically by the electronic diary, which must 
be checked prior to allocation at Visit 2. A subject who has not met average baseline pain 
intensity requirements (at least 4 average pain intensity ratings) due to lack of compliance with 
the electronic diary may be rescheduled for Visit 2 (1 time only), with appropriate re-training to 
ensure compliance with use of the electronic diary.
5.
In stable treatment and follow-up therapy for CRPS for at least 1 month prior to allocation to 
treatment (Visit 2). Subjects must have failed attempts with at least 2 available treatments for 
CRPS, 1 of which must have been a pharmacologic treatment.
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6.
Women of child-bearing potential must have a negative urine ß-HCG pregnancy test at Visit 1 
and must be using 2 forms of medically acceptable contraception, including at least 1 highly 
effective method of contraception with a low failure rate, defined as less than 1% per year (e.g., 
oral contraceptives or intrauterine device), and a second medically acceptable method such as 
use of condoms with spermicide by their male partner. A barrier method alone is not 
acceptable. Highly effective methods of contraception must be used for at least 1 month prior to 
Visit 2 and for the duration of the trial.
7.
Subjects must be able to communicate meaningfully, be able to differentiate with regard to 
location and intensity of the pain, and be able to answer the questions in the questionnaires used 
in this trial (assistance in filling out the questionnaires may be provided, if required due to 
motor or other physical impairment).
1.3.2
Exclusion criteria
Subjects will not be eligible for the trial if any of the following exclusion criteria apply. Subjects 
will only receive IMP if documentation is available showing that they do not meet any of these 
exclusion criteria.
1.
Evidence of severe renal impairment (estimated glomerular filtration rate [eGFR] less than 
30 mL/min/1.73 m2 using the 2009 Chronic Kidney Disease Epidemiology Collaboration 
[CKD-EPI] creatinine equation [Levey et al. 2009] or a urinary albumin to creatinine ratio 
[ACR] greater than 150 mg/g), based on central safety laboratory data obtained prior to Visit 2.
Note: a single repeat laboratory test is allowed.
2.
Serum calcium or magnesium outside of the central laboratory’s reference range, based on 
central safety laboratory data obtained prior to Visit 2 (2 repeat laboratory tests are allowed); a 
history of hypocalcemia or a metabolic disorder anticipated to increase risk for hypocalcemia 
(e.g., hypoparathyroidism); anticipated need for any new drug with known potential to cause 
hypocalcemia (e.g., aminoglycosides, new treatment with or dose adjustment of loop diuretics) 
during the trial.
Subjects on a stable dose of loop diuretics may receive treatment with IMP as long as no dosage 
increases in the diuretic medication are anticipated and calcium levels are in the reference 
range.
3.
Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL (75 nmol/L), based on 
central safety laboratory data obtained prior to Visit 2 (up to 4 repeat laboratory tests are 
allowed). Subjects with vitamin D deficiency should receive appropriate supplementation 
during the Enrollment Period. A vitamin D level of at least 30 ng/mL (75 nmol/L) must be 
documented prior to allocation to IMP.
4.
Corrected QT interval (according to Fridericia’s formula; QTcF) greater than 470 ms (average 
of 3 ECGs obtained at Visit 1) according to central ECG reading facility evaluation or QTcF 
greater than 470 ms at pre-dose ECG at Visit 2 according to the investigator’s judgment; serum 
potassium outside the central laboratory’s reference range at Visit 1 (a single repeat laboratory 
test is allowed); clinically unstable cardiac disease, including: unstable atrial fibrillation, 
symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or an 
indwelling pacemaker; evidence of complete left bundle branch block; complete 
atrioventricular block; history of Long QT Syndrome or a relative with this condition; or any
history of or other known risk factor for torsade de pointes.
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5.
Subjects receiving medications with a known risk of torsades de pointes within 7 days prior to 
allocation. Subjects receiving selective serotonin re-uptake inhibitor antidepressants (e.g., 
citalopram, escitalopram) are eligible if the QT interval values do not meet the exclusion 
criteria, the medication was started at least 1 month prior to Visit 1, the dose is stable, and the 
dose is anticipated to remain stable throughout the trial.
6.
Any prior use of a bisphosphonate for treatment of CRPS, any prior administration of a 
bisphosphonate within the previous year, anticipated requirement for treatment with a
bisphosphonate for another condition such as osteoporosis during the trial, or administration of 
denosumab (Prolia®) or other bone turnover suppressing drugs within 6 months prior to Visit 1.
7.
History of any allergic or hypersensitivity reaction to neridronic acid or other bisphosphonate, 
acetaminophen, or to vitamin D or calcium supplements.
8.
Recent tooth extraction or other invasive dental procedure (within 3 months prior to Visit 1), 
unhealed or infected extraction site, or significant dental/periodontal disease (e.g., impacted 
molars, severe tooth decay, foci of infection) that may pre-dispose to need for tooth extraction 
or other invasive dental procedures during the trial. Subjects with indeterminate, suspicious or 
unreliable dental history, in the opinion of the investigator, must undergo a dental examination 
prior to receiving treatment.
9.
Evidence of denture-related gum trauma or improperly fitting dentures causing injury.
10. Prior radiation therapy of the head or neck (within 1 year of Visit 1).
11. History of malignancy within 2 years prior to Visit 1, with the exception of basal cell 
carcinoma.
12. Use of nerve blocks, ketamine infusions, intravenous immunoglobulin, acupuncture, 
electromagnetic field treatment, or initiation/implementation of radiofrequency ablation or other 
sympathectomy procedures, or peripheral nerve stimulation within 6 weeks prior to Visit 1.
13. Evidence of current alcohol or drug abuse, or history of alcohol or drug abuse within 2 years of 
Visit 1, based on subject history and physical examination and according to the investigator’s 
judgment.
14. Any other severe medical condition, including severe depression, or any other severe mood 
disorder, that in the opinion of the investigator may affect efficacy or safety assessments or may 
compromise the subject’s safety during trial participation.
15. Women who are pregnant or breastfeeding.
16. Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-fold upper limit 
of normal, based on central safety laboratory data obtained at Visit 1, or current evidence of 
chronic liver disease. Safety laboratory testing may be repeated prior to Visit 2, and subjects 
will be allowed in the trial if results of 2 consecutive tests, at least 3 days apart, are less than or 
equal to 2-fold upper limit of normal.
17. Participation in another investigational drug trial within 3 months prior to Visit 1, or any 
previous trial involving neridronic acid.
18. Subject is engaged in litigation related to their disability from CRPS in which monetary gain or 
loss (or other compensation) may affect their objective participation in the trial.
19. Subjects taking forbidden concomitant medications/therapies or not being able to follow the 
rules of use of concomitant treatment (see Section 1.4.2).
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20. Subjects incapable of giving informed consent.
1.3.3
Criteria to continue into Treatment Period B
Safety laboratory tests will be taken at Visit 10. In case the serum calcium and/or vitamin D levels 
meet the exclusion criteria to continue into Treatment Period B, additional supplementation similar 
to the Enrollment Period is allowed between Visit 10 and Visit 11. In case of any safety laboratory 
retesting, the scheduling and time window of Visit 11 must not be affected.
The decision regarding whether a subject will continue into Treatment Period B will be taken at 
Visit 11, based on the following criteria:
•
A value of at least 4 on the pain intensity question (question number 29, GLOBAL07) of 
the PROMIS-29 profile at Visit 11.
•
The following exclusion criteria are not met:
−
Evidence of severe renal impairment (eGFR less than 30 mL/min/1.73 m2 using the 
2009 CKD-EPI creatinine equation [Levey et al. 2009] or a urinary ACR greater than 
150 mg/g), based on central safety laboratory data obtained prior to Visit 11. A single 
repeat laboratory test is allowed.
−
Corrected QT interval (QTcF) greater than 470 ms (average of 3 ECGs obtained at 
Visit 10) according to the central ECG reading facility evaluation or QTcF greater than 
470 ms at pre-dose ECG at Visit 11 according to the investigator’s judgment; serum 
potassium outside the central laboratory’s reference range at Visit 10 (a single repeat 
laboratory test is allowed); clinically unstable cardiac disease, including: unstable atrial 
fibrillation, symptomatic bradycardia, unstable congestive heart failure, active 
myocardial ischemia, or an indwelling pacemaker; evidence of complete left bundle 
branch block; complete atrioventricular block; any other known risk factor for torsade 
de pointes.
−
Subjects receiving medications with a known risk of torsades de pointes within 7 days 
prior to re-allocation.
−
Subjects taking forbidden concomitant medications/therapies or not being able to 
follow the rules of use of concomitant treatment (see Section 1.4.2).
−
Recent tooth extraction or other invasive dental procedure (within 3 months prior to 
Visit 11), unhealed or infected extraction site, or significant dental/periodontal disease 
(e.g., impacted molars, severe tooth decay, foci of infection) that may pre-dispose to 
need for tooth extraction or other invasive dental procedures during the further course 
of the trial.
−
Serum calcium or magnesium outside of the central laboratory’s reference range, 
despite appropriate supplementation between Visit 10 and Visit 11, based on the last 
central safety laboratory data obtained prior to Visit 11. One repeat laboratory test is
allowed.
−
Vitamin D deficiency prior to IMP re-allocation, defined as a 25(OH)D level less than 
30 ng/mL (75 nmol/L), based on the last central safety laboratory data obtained prior to 
Visit 11, i.e., inability to normalize 25(OH)D levels to at least 30 ng/mL (75 nmol/L) 
despite appropriate supplementation between Visit 10 and Visit 11. Two repeat 
laboratory tests are allowed (with a minimum interval of 3 days).
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−
Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-fold 
upper limit of normal, based on central safety laboratory data obtained at Visit 10, or 
current evidence of chronic liver disease. A single repeat laboratory test is allowed.
•
No other criterion for trial and/or IMP discontinuation is met.
The subjects and investigators will stay blinded to the treatment that the subject received in 
Treatment Period A.
If, at Visit 11, the criteria to continue into Treatment Period B are not met, the subjects will not 
receive any further IMP infusion and will continue with the follow-up visits Visit 16 and Visit 17. 
Subjects can only start Treatment Period B at Visit 11.
1.4
Trial treatments
1.4.1
Investigational medicinal products
The IMPs used in this trial are neridronic acid and matching placebo.
Investigational medicinal product is supplied in glass vials, each containing 108 mg sodium 
neridronate hemi hydrate (equivalent to 100 mg neridronic acid) or matching placebo in a total 
volume of 8 mL.
For subjects with no or mild renal impairment, the full contents of a single vial (8 mL) will be 
diluted in 500 mL normal saline and administered by slow intravenous infusion (240 minutes 
[maximum 260 minutes]) at Visit 2, Visit 3, Visit 4, and Visit 5, resulting in a total dose of 400 mg 
neridronic acid or matching placebo.
For subjects with no or mild renal impairment included in Treatment Period B, the full contents of a 
single vial (8 mL) will be diluted in 500 mL normal saline and administered by slow intravenous 
infusion (240 minutes [maximum 260 minutes]) at Visit 11, Visit 12, Visit 13, and Visit 14, 
resulting in a total dose of 400 mg neridronic acid.
All infusions must be performed at the trial site under the supervision of medical staff.
For subjects with moderate renal impairment, the following dose adjustments will be applicable:
CKD-EPI Stage 3a (eGFR 45 mL/min/1.73 m2 to <60 mL/min/1.73 m2)
6 mL of solution from a single vial (corresponding to neridronic acid 75 mg) will be diluted in 
500 mL normal saline and administered by slow intravenous infusion (240 minutes [maximum 
260 minutes]) at each treatment visit, resulting in a total dose of 300 mg neridronic acid or matching 
placebo.
CKD-EPI Stage 3b (eGFR 30 mL/min/1.73 m2 to <45 mL/min/1.73 m2)
5 mL of solution from a single vial (corresponding to neridronic acid 62.5 mg) will be diluted in 
500 mL normal saline and administered by slow intravenous infusion (240 minutes [maximum 
260 minutes]) at each treatment visit, resulting in a total dose of 250 mg neridronic acid or matching 
placebo.
For additional requirements related to the IMP infusion, please refer to Section 10.2 of the trial 
protocol.
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1.4.2
Prior/concomitant medications or therapies
Subjects participating in the trial must be on stable therapy prescribed for CRPS, including any 
multidisciplinary treatment program (e.g., consisting of physical therapy, occupational therapy, 
cognitive behavioral therapy, and/or graded motor imagery, including mirror feedback). Initiation of 
a new interdisciplinary treatment program during the trial is prohibited. Other allowed therapies, 
such as spinal cord stimulation, may be continued during the trial if they are stable for at least 
1 month prior to the start of treatment.
Subjects may continue treatment with allowed concomitant medications, including any stable 
analgesic regimens consisting of opioids and other analgesics, if they are on a stable, well-defined 
treatment regimen for at least 1 month before allocation to IMP and are anticipated to be able to 
maintain the treatment regimen up to and including Visit 8 at a minimum in the opinion of the 
investigator. A prescribed regimen including an as needed dosing schedule is permitted. A subject 
who does not take prescription analgesics but does take over-the-counter analgesics is permitted to 
participate if considered stable and anticipated to be able to continue taking only over-the-counter 
and non-prescription analgesics up to and including Visit 8 at a minimum. Over-the-counter 
analgesics must remain stable throughout the trial, up to and including Visit 8 at a minimum. After 
Visit 10, investigators should assess the further need of concomitant treatment for CRPS, in 
particular opioids, and evaluate if the dose or frequency of these treatments can be decreased, or if 
treatment can be stopped completely. Any resulting changes must be documented in the electronic 
case report form (eCRF). Subjects receiving treatment in Treatment Period B should remain on 
stable analgesic treatment (including over-the counter analgesics) between Visit 11 and Visit 16.
In the event a subject experiences a severe pain flare related to CRPS, trauma, or other reason, a 
course of short-acting analgesics, including opioids, may be prescribed for up to 2 weeks. The 
concomitant medication must be documented in the eCRF and the sponsor or sponsor’s 
representative (i.e., medical monitor) must be notified.
To alleviate the expected flu-like symptoms (acute phase reaction) potentially associated with the 
first intravenous administration of bisphosphonates, all subjects in both treatment groups must
receive oral acetaminophen (paracetamol) starting from approximately 1 hour prior to the first 
infusion of IMP and then approximately every 6 hours for the 72-hour period after the first infusion
in Treatment Period A and Treatment Period B. Commercially available doses of acetaminophen 
(paracetamol) can be used as available in the country where the trial is performed. However, the 
total dose of acetaminophen, including any other medications that contain acetaminophen, must not 
exceed the maximum allowed dose according to the local product information, and not more than 
4 g/day, due to acetaminophen’s known risks for hepatic toxicity. Non-steroidal anti-inflammatory 
drugs should not be used to alleviate the symptoms of the acute phase reaction due to their potential 
to cause acute changes in renal function, which may confound renal safety assessments.
All subjects will be provided with supplemental calcium and vitamin D, starting from Visit 1 and 
continuing through to the end of the trial. Calcium and vitamin D supplementation are considered 
standard of care for patients treated with bisphosphonates and other drugs that inhibit bone 
turnover. An appropriate daily supplement should be provided to subjects (recommended doses are 
500 mg/day to 1000 mg/day calcium and approximately 1000 IU/day vitamin D as locally 
authorized); if a subject is currently taking calcium and vitamin D supplements, these may be 
continued without need for additional supplementation, provided levels of supplementation are 
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similar to those recommended above. A combination product of calcium and vitamin D may be 
used. Subjects with vitamin D below 30 ng/mL (75 nmol/L) should receive higher doses of 
vitamin D during the Enrollment Period (e.g., 10 000 IU/day for 10 days), to meet the protocol-
required vitamin D levels prior to starting treatment at Visit 2 and prior to starting treatment at 
Visit 11. As repletion of vitamin D to these levels can be difficult, repeated laboratory testing for 
vitamin D is permitted during the Enrollment Period (up to a maximum of 4 times in 60 days) and 
between Visit 10 and Visit 11 (up to a maximum of 2 times). High doses of vitamin D should not be 
continued after the subject reaches vitamin D targets (supplementation should continue at the 
recommended daily dose of approximately 1000 IU/day).
With regard to the calcium and vitamin D supplements, the investigator should promote compliance 
by instructing the subject to take the supplements as prescribed and by stating that compliance is 
necessary for the subject’s safety. Subjects should be instructed to contact the investigator if they 
are unable for any reason to take the supplements as prescribed. When used as daily supplements in 
this trial, calcium and vitamin D are not to be considered as an IMP or a medical treatment for an 
adverse event.
1.4.2.1
Forbidden concomitant medications
The following medications are forbidden for the duration of the trial or as specified:
•
Any experimental or investigational treatment or therapy.
•
High-dose opioid analgesics (greater than 200 mg oral morphine equivalent daily dose) or 
combinations of opioids and benzodiazepines or any other treatment regimens that may 
have potential for significant opioid/sedatives side effects and that may be considered 
unstable or unsafe (according to the judgment of the investigator).
•
Concomitant use of drugs with the potential to cause hypocalcemia (e.g., aminoglycosides). 
Subjects on a stable dose of loop diuretics may be allocated to IMP as long as no dosage 
increases in the diuretic medication are anticipated and calcium levels are in the reference 
range.
•
Oral, intravenous, or intramuscular bisphosphonates, calcitonin, denosumab, anti-
angiogenic drugs or other bone-active drugs (e.g., teriparatide).
•
Drugs with risk for torsades de pointes as specified:
−
Drugs with a known risk of torsades de pointes within 7 days prior to allocation and 
throughout the trial.
−
With the following exceptions: selective serotonin re-uptake inhibitor antidepressants 
(e.g., citalopram, escitalopram), if QT interval values met entry criteria, subjects were 
on a stable dose for at least 1 month prior to Visit 1, and doses are expected to stay 
stable throughout the trial.
•
Concomitant administration of non-steroidal anti-inflammatory drugs or any other agents 
with the potential to interfere with the assessment of potential changes in renal function 
(e.g., angiotensin converting enzyme inhibitors) until 2 weeks after the last IMP 
administration per treatment period, unless subjects are receiving a stable dose for at least 
1 month prior to Visit 1. Non-steroidal anti-inflammatory drugs should not be used to 
alleviate the symptoms of the acute phase reaction.
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•
Use of nerve blocks, ketamine infusions, intravenous immunoglobulin, acupuncture, 
electromagnetic field treatment, initiation/implementation of radiofrequency ablation or 
other sympathectomy procedures, or peripheral nerve stimulation, within 6 weeks prior to 
Visit 1 and for the entire duration of the trial.
•
Use of systemic steroids starting 2 weeks prior to Visit 1 and for the entire duration of the 
trial.
1.5
Statistical analyses
The primary analysis will be performed once all subjects have completed Visit 11 (Week 26), 
including database lock and unblinding. The results from this 26-week analysis will be reported in 
an interim integrated clinical trial report.
The final analysis of this trial, including Treatment Period B and Follow-up Period 2, will be 
performed after the last subject has completed the trial and the database has been locked.
1.5.1
Sample size rationale
The sample size is based on a statistical test of the superiority of 400 mg neridronic acid versus 
placebo in the primary endpoint. The null hypothesis of no effect, H0: 0 ≤μ400 - μ0, is tested against 
the alternative hypothesis H1: μ400 - μ0<0. (Note: A pain reduction will be analyzed as a negative 
change from baseline. An effective treatment will lead to reduced pain and, hence, to a negative 
mean change from baseline, μ<0).
For a difference in the means of μ400 - μ0 = -1.0 points on the NRS, assuming a standard deviation 
of 2.0 points on the NRS and a 1-sided significance level of 2.5% (α = 0.025), 86 subjects per arm 
will be required to provide at least 90% power (1-β = 0.9) to reject the null hypothesis. To 
compensate for a slight decrease in power due to an optional futility interim analysis, a total of 
180 subjects (90 subjects per arm) are planned to be allocated to treatment.
1.5.2
Subject populations
Enrolled Set:
The Enrolled Set includes all subjects who signed the informed 
consent form.
Allocated Set:
The Allocated Set includes all subjects who are allocated to treatment.
Safety Set:
All subjects with at least 1 IMP administration, including any partial 
infusion.
Full Analysis Set:
All subjects allocated with at least 1 IMP administration, including any 
partial infusion.
Pharmacokinetic Set:
All subjects with at least 1 evaluable pharmacokinetic concentration.
Pharmacodynamic Set:
All treated subjects with at least 1 non-missing value for at least 1 of 
the bone turnover markers.
1.5.3
Statistical methods and analysis
The analysis of primary and secondary efficacy endpoints is described in the subsections below. All 
other efficacy endpoints will be descriptively summarized in the Full Analysis Set. Confirmatory 
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testing will be performed for the primary endpoint and for selected secondary endpoints. Further 
analyses may be done, including statistical hypothesis tests, but all analyses will be exploratory in 
nature and will not provide confirmatory evidence.
Subject disposition as well as demographic and baseline data and other subject characteristics, e.g., 
medical history and prior and concomitant medications, will be descriptively summarized for the 
Full Analysis Set and the Safety Set.
Adverse events, laboratory values, ECG, vital signs, and further safety parameters will be 
summarized descriptively for the Safety Set. All laboratory parameters will be collected both in SI 
units and US conventional units. All parameters will be reported in SI units and, in addition, 
selected laboratory parameters will be reported also in US conventional units (dual reporting).
Pharmacokinetic concentrations will be analyzed in the Pharmacokinetic Set. Descriptive statistics 
of the observed neridronic acid plasma concentrations at the planned time windows will be created. 
Owing to the sparse sampling and the random time points, no derivation and analysis of non-
compartmental pharmacokinetic parameters is foreseen.
Bone turnover marker values will be descriptively summarized by parameter for the 
Pharmacodynamic Set.
Health economics and work productivity data will be summarized descriptively for the Full 
Analysis Set.
Analysis of sIL-2R concentrations will be summarized descriptively for the Safety Set.
All efficacy and safety data evaluated during Treatment Period B and Follow-up Period 2 will be 
analyzed descriptively separately for subjects who are treated in Treatment Period B and subjects 
who are not treated. For subjects treated in Treatment Period B, analyses will be performed for 
subjects initially treated with placebo and subjects initially treated with neridronic acid.
1.5.3.1
Primary endpoint
See Section 1.2 for the definition of the primary endpoint.
For the primary objective of the trial, the primary estimand is the difference in means of the primary 
efficacy endpoint of 400 mg intravenous neridronic acid compared to placebo for all allocated and 
treated subjects. This treatment policy or de facto estimand measures the effect of neridronic acid 
regardless of adherence to treatment or protocol.
The primary estimand will be estimated by the analysis of the primary efficacy endpoint for the Full 
Analysis Set. The primary analysis will fit a mixed model for repeated measures (MMRM) to the 
change from baseline in the average pain intensity scores from Week 1 to Week 12 recorded once
daily in the electronic diary, including the covariate baseline pain intensity score, and the factors 
geographic region, week, treatment, and treatment-by-week interaction as fixed effects, and an 
unstructured covariance matrix to model the covariance structure of the repeated measurements.
The primary efficacy analysis will be performed using the contrast, i.e., the mixed model Wald test, 
of neridronic acid 400 mg versus placebo at Week 12 of the treatment, week and treatment-by-week 
interaction term of the mixed effects model described above. Model-based parameter estimates, 
standard errors, 95% confidence intervals, and p-values will be tabulated. This analysis will be 
performed using only the observed values without imputation of missing values.
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Additional sensitivity analyses will be performed to assess the robustness of primary analysis 
results. Sensitivity analyses will include the imputation of missing pain intensity scores using 
different pattern mixture models (PMMs).
A descriptive summary of the weekly averages and the changes from baseline will be generated by 
treatment group. Graphical displays will be used if appropriate.
1.5.3.2
Secondary efficacy endpoints
All secondary efficacy endpoints will be analyzed for the Full Analysis Set.
Average pain intensity
The change from baseline in the average pain intensity, recorded on the tablet computer, will be 
analyzed with an MMRM, including the covariate baseline pain intensity score, and the factors 
geographic region, week, treatment, and treatment-by-week interaction as fixed effects, and subject 
as random effect. An unstructured covariance matrix will be used to model the covariance structure.
The analysis will be performed using the contrast, i.e., the mixed model Wald test, of 400 mg 
neridronic acid versus placebo at Week 26 of the treatment, week and treatment-by-week 
interaction term of the mixed effects model described above. Model-based parameter estimates, 
standard errors, 95% confidence intervals, and p-values will be tabulated. This analysis will be 
performed using the observed values without imputation of missing values.
Pain response to treatment
Pain response to treatment, defined as an at least 30% decrease from baseline in average pain 
intensity, recorded on the tablet computer, will be derived. If a subject shows a worsening or the 
pain intensity score for the respective visit is missing then the subject will be considered a pain non-
responder for the respective visit. A logistic regression model at Week 12 and Week 26 will be 
fitted to the data, including the covariate baseline pain intensity score, and the factors geographic 
region, and treatment as fixed effects. Model-based parameter estimates, standard errors, 95% 
confidence intervals, and p-values for the odds ratio at Week 12 and Week 26 between 400 mg 
neridronic acid and placebo will be tabulated.
The analysis of pain response to treatment will include a cumulative responder analysis at Week 12, 
Week 26, and Week 52, where responder rates will be calculated for different percentage thresholds 
for decrease from baseline in average pain intensity.
Dynamic mechanical allodynia
The change from baseline in the DMA will be analyzed using a similar model as for average pain 
intensity. Only subjects with allodynia at baseline, i.e., a DMA score greater than 0 on the 0 to 10 
NRS, will be included in the analysis.
Pressure pain threshold
The change from baseline in the ratio of the PPT in the affected limb to the PPT in the unaffected 
limb for the thenar muscle/abductor hallucis muscle will be analyzed using a similar model as for 
average pain intensity. Only subjects with deep somatic pain (PPT ! 300 kPa) in the affected limb at 
baseline will be included in the analysis.
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Edema
The change from baseline in edema will be analyzed using a similar model as for average pain 
intensity. Only subjects with presence of the CRPS sign “asymmetric edema” at baseline will be 
included in the analysis.
1.5.3.3
Missing data handling
Diligent attempts will be made to limit the amount of missing data in the primary efficacy endpoint. 
Efforts will be made to follow-up subjects who discontinue treatment and to collect the primary 
efficacy endpoint for the statistical analysis.
The primary analysis using the MMRM is based on the missing-at-random (MAR) assumption. For 
the treatment policy or de facto estimand, the MAR assumption is justified for neridronic acid 
owing to the long half-life in bone and the anticipated persistent effect over the 12-week trial 
period. It can be assumed that the effect of neridronic acid continues after the treatment period is 
completed, and it also persists after the treatment period regardless of trial completion or early 
discontinuation. Therefore, the response of discontinued subjects will not change if the subjects 
continue to receive the stable therapy that they receive during the 12-week trial period up to Visit 8. 
If subjects change their treatment after discontinuation from the trial, it is nevertheless reasonable to 
assume that their response is not significantly altered as there are currently no established effective 
treatments. Hence, the MAR assumption is considered a plausible missingness mechanism for the 
primary estimand in the case of neridronic acid.
The MAR assumption cannot be verified based on data observed in the trial. Deviations from MAR 
cannot be excluded and several plausible missing-not-at-random (MNAR) assumptions will be 
investigated to assess their impact. MNAR assumptions will be defined via PMMs specifying the 
distribution of missing values, e.g., for subjects discontinuing before the end of the trial. Plausible 
PMMs for the primary estimand are placebo multiple imputation (PMI) and the delta shift method. 
Placebo multiple imputation is a reference-based approach based on the copy reference method. It 
models the means of missing values in the active arm based on the means observed in the placebo 
arm (reference arm). The method assumes that the response of discontinued subjects in the active 
arm gradually approaches the response in the placebo arm and eventually no effect of neridronic 
acid persists after a subject discontinues. For neridronic acid this appears conservative in light of the 
anticipated persistent effect.
The delta shift method models the means of missing values in the active arm by adding a pre-
specified value Δ to the observed means in the active arm. The method includes a tipping point 
analysis, which is defined as the delta that must be added in order to overturn conclusions from the 
primary analysis from statistically significant to statistically insignificant. The method assumes that 
discontinued subjects in the active arm have higher pain compared to subjects who stay in the trial. 
Again this seems conservative if persistence of effect can be assumed for neridronic acid.
Overall, the 2 PMMs can be considered more conservative than MAR because they model missing 
pain intensity scores in the active arm using higher mean values than the means actually observed, 
whereas the placebo arm is not changed. In this way, neridronic acid is effectively penalized under 
these assumptions. 
In summary, for neridronic acid the MAR assumption seems to be the most plausible missingness 
assumption for analyses estimating the primary estimand. It will be supplemented by sensitivity 
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analyses based on MNAR assumptions representing plausible and reasonably conservative 
deviations from MAR.
1.5.3.4
Confirmatory testing strategy for secondary endpoints
A confirmatory testing procedure will be used for testing of the superiority of neridronic acid 
400 mg versus placebo with respect to the primary and selected secondary efficacy endpoints
(change from baseline to Week 26 in the average pain intensity, change from baseline to Week 12 
in the pain intensity level of DMA, change from baseline to Week 12 in the PPT ratio, and change 
from baseline to Week 12 in the ratio of figure of eight measurements).
First, the primary endpoint will be tested at a one-sided level α = 2.5%. If the first test is statistically 
significant, the 4 secondary endpoints will be tested in a second stage.
To control for the family-wise type I error rate at the one-sided 2.5% level, a hybrid Hochberg-
Hommel step-up procedure (hybrid-0 procedure in Gou et al. 2014) will be applied. The testing 
procedure uses the ordered p-values p(1) ≥ p(2) ≥ p(3) ≥ p(4). At first, if the largest p-value p(1) ≤α, 
then all 4 hypotheses are rejected. Otherwise the associated null hypothesis H(1) is accepted and 
testing proceeds to the next step. In general, at Step i = 2,..4, if  p(i) ≤ ciα, then any hypothesis with 
p-value ≤ diα will be rejected and testing stops; otherwise the null hypothesis H(i) and testing 
continues at the next step. At Step 4, the null hypothesis H(4) is rejected if p(4) ≤ α/4; otherwise H(4)
is accepted. The constants used in the testing procedure are defined by ci = (i+1)/(2i) and di = 1/i
and are given in the table below.
i
1
2
3
4
ci
1
3/4
2/3
5/8
di
1
1/2
1/3
1/4
This semiparametric multiple testing procedure controls the family-wise error rate in the strong 
sense if the test statistics follow a multivariate normal distribution with non-negative correlation 
coefficients (Gou et al. 2014) which can be assumed for the investigated 4 efficacy endpoints.
1.5.3.5
Subgroup analyses
Subgroup analyses may be done if appropriate and will be specified in the statistical analysis plan.
1.5.3.6
Pooling of sites
Individual sites will be pooled by geographic region.
1.5.3.7
Interim analysis
An interim analysis is planned after a combined total of approximately 80 subjects in the two 
Phase III trials, KF7013-02 and KF7013-04, have completed Week 12 of treatment and the required 
data is available in the databases. The interim analysis is for futility only and will be non-binding. 
The futility criterion will be based on the unblinded comparison of the primary endpoint and will be 
calculated using identical methods as for the final analysis. If the observed difference in the means 
of μ400 - μ0 is ≥ -0.3 points on the NRS, the null hypothesis will not be rejected and the 
recommendation will be to stop both trials. The interim analysis will be performed by an 
independent statistical analysis unit not otherwise involved in the conduct of the trial and the result 
will only state the recommendation to stop or continue the Phase III program. No unblinded 
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information will be disseminated to the trial teams. Pending recruitment rates of both trials, it may 
be decided to forgo the interim analysis or conduct it a different point in time. As the interim 
analysis will be for futility only, no inflation of the type I error will occur.
1.6
Pharmacometric analyses
Sparse pharmacokinetic sampling is performed in this trial. A previously developed population 
pharmacokinetics model will be updated using the plasma concentration-time data collected in this 
trial.
An exploratory evaluation of the potential relationships between neridronic acid exposure levels and 
the primary efficacy endpoint will be performed.
Modeling and simulation analyses will be performed by sponsor personnel or by authorized sponsor 
delegates. Details will be described in pharmacometric analysis plans.
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1.7
Schedules of events
1.7.1
Visit 1 to Visit 10
Trial procedure
Enrollment 
Period
Treatment Period A
Follow-up Period 1
Visit 1 a
Visit 2
Visit 3 b
Visit 4 b
Visit 5 b
Visit 6
Visit 7
Visit 8 c
Visit 9
Visit 10
Day -60
to Day -8
Day 1
Day 4
(±1 day)
Day 7
(±1 day)
Day 10
(±1 day)
Day 15/
Week 2
(±2 days)
Day 43/
Week 6
(±3 days)
Day 85/
Week 12
(+7 days)
Day 113/
Week 16
(±4 days)
Day 155/
Week 22
(±4 days)
Obtain written informed consent d
X
Record demographic data e
X
Record medical history
X
Record CRPS history f
X
Record dental history g
X
Record physical examination outcome h
X
X
X
Record body weight
X
Record vital signs i
X
X
X
X
X
X
X
X
X
X
Record 12-lead ECG j
X
X
X
X
X
X
Record prior/concomitant medications and 
therapies k
X
X
X
X
X
X
X
X
X
X
Record adverse events l
X
X
X
X
X
X
X
X
X
X
Take blood for safety laboratory testing
X
X
X
X
X
X
X
X
X
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Trial procedure
Enrollment 
Period
Treatment Period A
Follow-up Period 1
Visit 1 a
Visit 2
Visit 3 b
Visit 4 b
Visit 5 b
Visit 6
Visit 7
Visit 8 c
Visit 9
Visit 10
Day -60
to Day -8
Day 1
Day 4
(±1 day)
Day 7
(±1 day)
Day 10
(±1 day)
Day 15/
Week 2
(±2 days)
Day 43/
Week 6
(±3 days)
Day 85/
Week 12
(+7 days)
Day 113/
Week 16
(±4 days)
Day 155/
Week 22
(±4 days)
Collect urine for quantitative urinalysis at 
the central laboratory
X
X
X
X
X
X
X
X
X
Perform dipstick urinalysis
X
X
X
X
X
X
X
X
X
Perform semi-quantitative dipstick 
urinalysis for urinary ACR
X
X
X
X
Perform a urine ß-HCG pregnancy test m
X
X
X
X
X
X
Perform urine drugs of abuse testing
X
X
Complete the assessment of the signs and 
symptoms of CRPS
n
X
X
X
X
X
X
Dispense subject trial card
X
Dispense calcium and vitamin D 
supplements
o
X
Review inclusion/exclusion criteria p
X
X
Dispense electronic diary q
X
Training and compliance assessment for 
electronic diary 
X bb
X
X
X
X
X
X
X cc
X
X
Allocate to IMP r
X
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Trial procedure
Enrollment 
Period
Treatment Period A
Follow-up Period 1
Visit 1 a
Visit 2
Visit 3 b
Visit 4 b
Visit 5 b
Visit 6
Visit 7
Visit 8 c
Visit 9
Visit 10
Day -60
to Day -8
Day 1
Day 4
(±1 day)
Day 7
(±1 day)
Day 10
(±1 day)
Day 15/
Week 2
(±2 days)
Day 43/
Week 6
(±3 days)
Day 85/
Week 12
(+7 days)
Day 113/
Week 16
(±4 days)
Day 155/
Week 22
(±4 days)
Check trial discontinuation criteria
X
X
X
X
X
X
X
X
X
Check IMP suspension criteria s
X
X
X
X
Administer IMP t
X
X
X
X
Ask the subject to record the average, worst, 
and current pain on the tablet computer at 
the site y
X
X
X
X
X
Measure edema, DMA, PPT, and AROM aa
X
X
X
Ask the subject to complete the
EQ-5D-5L
X
X
Ask the subject to complete the PROMIS-
29 profile
X
X
X
X z
X z
Ask the subject to complete the PROMIS-
EDDEP39
X
X
X
Ask the subject to complete the 
6 neuropathic questions of the SF-MPQ-2
X
X
X
Ask the subject to complete the PCS
X
X
X
Ask the subject to complete the PSEQ
X
X
X
Ask the subject to complete the PGI-S
X
X
X
X
X
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Trial procedure
Enrollment 
Period
Treatment Period A
Follow-up Period 1
Visit 1 a
Visit 2
Visit 3 b
Visit 4 b
Visit 5 b
Visit 6
Visit 7
Visit 8 c
Visit 9
Visit 10
Day -60
to Day -8
Day 1
Day 4
(±1 day)
Day 7
(±1 day)
Day 10
(±1 day)
Day 15/
Week 2
(±2 days)
Day 43/
Week 6
(±3 days)
Day 85/
Week 12
(+7 days)
Day 113/
Week 16
(±4 days)
Day 155/
Week 22
(±4 days)
Ask the subject to complete the WPAI: 
CRPS u
X
X
Collect information for medical resources 
utilization and health economics u
X
X
Take blood for pharmacokinetic evaluationv
X
X
X
X
X
Take blood for bone turnover marker 
evaluation w
X
X
X
X
X
Take blood for sIL-2R testing
X
X
Take blood for pharmacogenetic testing x
X
Take blood for omics testing x
X
X
Ask the subject to complete the PGIC
X
X
X
X
a) The Enrollment Period consists of an Enrollment Visit (Visit 1) prior to Day -7 and a baseline pain assessment phase from Day -7 to Day -1 during which subjects will report 
pain intensity ratings in the electronic diary. These pain intensity ratings will be used to calculate the baseline pain intensity score. Additional visits are allowed during the 
Enrollment Period to confirm normal laboratory values or ensure protocol targets for vitamin D (for details of repeat testing, see Section 1.3.2). If the Enrollment Period exceeds 
30 days, determination of hematology and clinical chemistry parameters should be repeated to confirm there is no major change in the subject’s overall health status prior to 
allocation.
aa) Edema will only be measured in subjects reporting asymmetric edema as part of the assessment of the signs and symptoms of CRPS at baseline (Visit 2). The AROM will 
only be measured in subjects reporting decreased AROM as part of the assessment of the signs and symptoms of CRPS at baseline (Visit 2).
b) Infusion visits should be separated by 3-day intervals to the extent possible (i.e., Day 1, Day 4, Day 7, and Day 10). Infusion visits on consecutive days are not allowed. The 
full dosing period must not exceed 21 days from the first infusion (Visit 2). To facilitate scheduling, the interval between infusion visits may be adapted, provided the 21 day time 
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period is not exceeded and discontinuation criteria can be assessed. In case of suspension of treatment due to a suspected safety concern or a visit scheduling difficulty, 
resumption of treatment is allowed upon resolution of findings, with sponsor agreement. In case of interruption or suspension of treatment, the first follow-up visit (Visit 6) 
should be scheduled at 4 days (±2 days) after the last infusion visit. All subsequent visits must remain as originally scheduled relative to Visit 2 (e.g., Visit 7 occurs at 42 days 
[6 weeks] ±3 days after Visit 2). No more than 4 infusions are allowed in Treatment Period A; any partial infusion (exceeding 20 mL) must be counted as 1 infusion.
bb) Compliance assessment for electronic diary not required at Visit 1.
c) Visit 8 must not occur prior to Day 85 in order for the subjects to have complete electronic diary data through Week 12 for the calculation of the primary endpoint.
cc) Training on electronic diary as, from Week 12, the electronic diary will ask for weekly assessments of pain intensity.
d) The specific informed consent form for pharmacogenetic and omics sampling should preferably be signed at Visit 1, but has to be signed at the latest at Visit 2 before the 
sample is taken.
e) Demographic data will include the date of signing the informed consent form, sex, race/ethnicity, age, height, and body mass index.
f) History of CRPS includes the date, location, and type of precipitating event (including any information on whether there was a major nerve injury); date of onset of symptoms; 
date of prior CRPS diagnosis; specific location of signs and symptoms where the diagnostic criteria were applied, and information on any other/prior occurrence of CRPS or other 
body regions considered to be affected by CRPS.
g) Dental history will include: date of last dental visit; dental extractions and other invasive dental surgery in the past 3 months prior to the Enrollment Visit; current evidence of 
dental or periodontal disease, gum injury due to dentures, or other dental history that may pre-dispose to risk of medication-related osteonecrosis of the jaw.
h) After Visit 1, record any changes from the prior assessment.
i) At Visit 2 to Visit 5, vital signs will be taken prior to infusion and after infusion.
j) All ECGs will be recorded in triplicate. For Visit 2 to Visit 5, triplicate ECGs will be recorded twice: at least 15 minutes prior to the infusion and at least 15 minutes after the 
infusion.
k) Dose and dosing frequency data must be recorded.
l) Subjects should be queried for any events occurring since the prior visit; any events noted at Visit 1 should be documented as medical history or as part of physical examination 
results.
m) For women of child-bearing potential, a negative dipstick urine pregnancy test result must be obtained prior to each infusion. Additional pregnancy tests to those specified 
may be performed if required by local law or regulations.
n) Signs and symptoms of CRPS will be assessed at Visit 1 to confirm the diagnosis of CRPS according to the Budapest clinical criteria. Budapest criteria for ongoing, 
disproportionate pain and a lack of other diagnosis that better explains the signs and symptoms must also be confirmed at Visit 1. Assessments of signs and symptoms of CRPS at 
all subsequent visits will use symptom recall for the past 48 hours for the determination of the CRPS Severity Score.
o) Vitamin D and calcium supplements will be dispensed to subjects for use during the trial; subjects who are receiving appropriate doses of these supplements may continue 
without requirement for additional supplementation.
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p) Compliance with inclusion and exclusion criteria must be confirmed before allocation to IMP. At Visit 2, the baseline average pain intensity score must be confirmed prior to 
allocation by checking the electronic diary, which will provide an automatic calculation. A baseline average pain intensity score of at least 4 on the 11-point NRS is required. A 
subject who has not met average baseline pain intensity requirements (at least 4 average pain intensity ratings) due to lack of compliance with the electronic diary may be 
rescheduled for Visit 2 (1 time only), with appropriate re-training to ensure compliance with use of the electronic diary. Subjects who do not meet eligibility criteria due to an 
inadequate baseline average pain intensity score (less than 4 on the NRS) will be excluded from the trial.
q) The electronic diary is to be returned at Visit 17 or at the Early Termination Visit in the case of early discontinuation from the trial.
r) Allocation must be performed using the interactive response technology system.
s) Subjects must be assessed prior to each infusion and IMP should be suspended if a suspension criterion is met. This includes assessment for signs and symptoms of ocular 
inflammation, signs of proteinuria, and signs of dehydration. Subjects must be well hydrated prior to the start of infusions.
t) All baseline measurements (including blood sampling for hematology, clinical chemistry, urinalysis; ECG; vital signs; physical examination) must be completed before the start 
of the first infusion of IMP. Investigational medicinal product must be diluted in 500 mL saline and administered by slow intravenous infusion (the infusion time must be at least 
240 minutes [up to a maximum of 260 minutes]).
u) At US sites only.
v) For Visit 2 and Visit 5, 1 blood sample for pharmacokinetic evaluation should be taken between 5 minutes and 10 minutes prior to the start of the infusion, 1 blood sample 
120 minutes after the start of the infusion, and 1 blood sample 60 minutes after the end of the infusion.
For Visit 3 and Visit 4, 1 blood sample for pharmacokinetic evaluation should be taken between 5 minutes and 10 minutes prior to the start of the infusion and 1 blood sample 
between 5 minutes and 10 minutes after the end of the infusion.
Blood samples for pharmacokinetics must be taken from a limb different from that used for the infusion and must not be taken from the infusion line.
At Visit 6, the sample can be taken at any time point during the visit.
w) Blood samples for bone turnover markers (C-terminal telopeptide of type I collagen, bone alkaline phosphatase, and procollagen type I amino-terminal propeptide) should be 
obtained in the morning after an overnight fast.
x) The blood sample for pharmacogenetic and omics testing will be collected in consenting subjects.
y) Worst and average pain intensity ratings will be based on a 24-hour recall period.
z) Only the pain intensity question (question number 29, GLOBAL07) of the PROMIS-29 profile should be recorded.
AROM = active range of motion, ß-HCG = beta-human chorionic gonadotropin, CRPS = complex regional pain syndrome, DMA = dynamic mechanical allodynia, 
ECG = electrocardiogram, EQ-5D-5L = EuroQol-5 Dimension-5 level, IMP = investigational medicinal product, NRS = numerical rating scale, omics = a generic term referring 
to analysis techniques like pharmacogenetics, genomics, epigenetics, transcriptomics, proteomics, metabolomics, PCS = Pain Catastrophizing Scale, PGIC = Patient Global 
Impression of Change, PGI-S = Patient Global Impression of Severity, PPT = pressure pain threshold, PROMIS-29 profile = Patient-Reported Outcomes Measurement 
Information System (PROMIS®)-29 profile version 2.0, PROMIS-EDDEP39 = Question EDDEP39 of the PROMIS Item Bank version 1.0 – Emotional Distress – Depression, 
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PSEQ = Pain Self Efficacy Questionnaire, SF-MPQ-2 = Short-Form McGill Pain Questionnaire 2, sIL-2R = soluble interleukin-2 receptor, WPAI = Work Productivity and 
Activity Impairment.
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f) All ECGs will be recorded in triplicate. For Visit 11 to Visit 14, triplicate ECGs will be recorded twice: at least 15 minutes prior to the infusion and at least 15 minutes after the 
infusion.
g) Dose and dosing frequency data must be recorded.
h) Subjects should be queried for any events occurring since the prior visit.
i) For women of child-bearing potential, a negative dipstick urine pregnancy test result must be obtained prior to each infusion. Additional pregnancy tests to those specified may 
be performed if required by local law or regulations.
j) Assessments of signs and symptoms of CRPS at all visits will use symptom recall for the past 48 hours for the determination of the CRPS Severity Score.
k) Allocation must be performed using the interactive response technology system.
l) Subjects must be assessed prior to each infusion and IMP should be suspended if a suspension criterion is met. This includes assessment for signs and symptoms of ocular 
inflammation, signs of proteinuria, and signs of dehydration. Subjects must be well hydrated prior to the start of infusions.
m) All measurements (including blood sampling for hematology, clinical chemistry, urinalysis; ECG; vital signs; physical examination) must be completed before the start of the 
first infusion of IMP. Investigational medicinal product must be diluted in 500 mL saline and administered by slow intravenous infusion (the infusion time must be at least 
240 minutes [up to a maximum of 260 minutes]).
n) At US sites only.
o) For Visit 11 and Visit 14, 1 blood sample for pharmacokinetic evaluation should be taken between 5 minutes and 10 minutes prior to the start of the infusion, 1 blood sample 
120 minutes after the start of the infusion, and 1 blood sample 60 minutes after the end of the infusion.
For Visit 12 and Visit 13, 1 blood sample for pharmacokinetic evaluation should be taken between 5 minutes and 10 minutes prior to the start of the infusion and 1 blood 
sample between 5 minutes and 10 minutes after the end of the infusion.
Blood samples for pharmacokinetics must be taken from a limb different from that used for the infusion and must not be taken from the infusion line.
At Visit 15, the sample can be taken at any time point during the visit.
p) Blood samples for bone turnover markers (C-terminal telopeptide of type I collagen, bone alkaline phosphatase, and procollagen type I amino-terminal propeptide) should be 
obtained in the morning after an overnight fast.
q) Compliance with the criteria to continue into Treatment Period B must be confirmed before allocation to IMP. The pain intensity question (question number 29, GLOBAL07) 
of the PROMIS-29 profile has to have a value of at least 4 at Visit 11. Subjects who do not meet the criteria to continue into Treatment Period B will continue with the Follow-up 
Period 2.
r) Worst and average pain intensity ratings will be based on a 24-hour recall period.
s) Only for the subjects going into Treatment Period B.
t) Edema will only be measured in subjects reporting asymmetric edema as part of the assessment of the signs and symptoms of CRPS at baseline (Visit 2). The AROM will only 
be measured in subjects reporting decreased AROM as part of the assessment of the signs and symptoms of CRPS at baseline (Visit 2).
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u) The blood sample for omics testing will be collected in consenting subjects.
v) No training needed at Visit 17.
AROM = active range of motion, ß-HCG = beta-human chorionic gonadotropin, CRPS = complex regional pain syndrome, DMA = dynamic mechanical allodynia, 
ECG = electrocardiogram, EQ-5D-5L = EuroQol-5 Dimension-5 level, IMP = investigational medicinal product, omics = a generic term referring to analysis techniques like 
pharmacogenetics, genomics, epigenetics, transcriptomics, proteomics, metabolomics, PCS = Pain Catastrophizing Scale, PGIC = Patient Global Impression of Change, PGI-
S = Patient Global Impression of Severity, PPT = pressure pain threshold, PROMIS-29 profile = Patient-Reported Outcomes Measurement Information System (PROMIS®)-29 
profile version 2.0, PROMIS-EDDEP39 = Question EDDEP39 of the PROMIS Item Bank version 1.0 – Emotional Distress – Depression, PSEQ = Pain Self Efficacy 
Questionnaire, SF-MPQ-2 = Short-Form McGill Pain Questionnaire 2, sIL-2R = soluble interleukin-2 receptor, WPAI = Work Productivity and Activity Impairment.
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1.8
References
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation 
to estimate glomerular filtration rate. Ann Intern Med 2009; 150 (9): 604-12.
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2
TABLE OF CONTENTS
1
PROTOCOL SYNOPSIS
2
1.1
Trial design
2
1.1.1
Flow diagram summary of the trial
2
1.1.2
Brief description of the sequence and duration of all trial periods
3
1.2
Trial objectives, endpoints, and outcomes
3
1.3
Trial subjects – the population to be studied
6
1.3.1
Inclusion criteria
6
1.3.2
Exclusion criteria
7
1.3.3
Criteria to continue into Treatment Period B
9
1.4
Trial treatments
10
1.4.1
Investigational medicinal products
10
1.4.2
Prior/concomitant medications or therapies
11
1.5
Statistical analyses
13
1.5.1
Sample size rationale
13
1.5.2
Subject populations
13
1.5.3
Statistical methods and analysis
13
1.6
Pharmacometric analyses
18
1.7
Schedules of events
19
1.7.1
Visit 1 to Visit 10
19
1.7.2
Visit 11 to Visit 17
26
1.8
References
32
2
TABLE OF CONTENTS
33
LIST OF IN-TEXT TABLES
38
3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
38
3.1
Abbreviations
38
3.2
Definition of terms
40
4
ETHICS
41
4.1
Independent ethics committees or institutional review boards
41
4.2
Subject information and informed consent
41
4.3
Informing the subject’s healthcare provider
42
5
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
42
5.1
Investigators and trial site personnel
42
5.1.1
Investigators
42
5.1.2
Trial site personnel assigned trial-related duties
43
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5.2
Contract research organizations
43
5.3
The sponsor and sponsor’s personnel
43
6
INTRODUCTION AND TRIAL BACKGROUND
43
6.1
Introduction
43
6.2
Background to the IMP
44
6.3
Relevant non-clinical and clinical data
44
6.4
Trial rationale
45
7
TRIAL OBJECTIVES AND ENDPOINTS
45
8
TRIAL DESIGN
46
8.1
Discussion of the trial design
46
8.1.1
Rationale for the trial population
47
8.1.2
Rationale for the investigational medicinal products and the selected 
doses
48
8.1.3
Rationale for the number and the frequency of visits/assessments
48
8.1.4
Background and rationale regarding pharmacogenetic and omics testing
48
8.2
Benefit/risk analysis
48
9
SUBJECT ENROLLMENT AND TRIAL DISCONTINUATION
53
9.1
Subject enrollment procedure
53
9.2
Inclusion/exclusion criteria
53
9.3
Subject discontinuation from the trial or IMP
53
9.3.1
Subject discontinuation from the trial
53
9.3.2
Subject discontinuation from the IMP
54
9.3.3
Procedure for the handling of discontinued subjects
56
9.3.4
Premature termination or suspension of the trial
57
10
TRIAL TREATMENTS
58
10.1
Investigational medicinal products
58
10.1.1
Identity and composition – neridronic acid
58
10.1.2
Identity and composition – matching placebo
58
10.1.3
Preparation
58
10.1.4
Packaging and labeling
58
10.1.5
Delivery, storage, and disposal
58
10.2
Administration of investigational medicinal products
59
10.3
Method of assigning subjects to treatment (allocation)
60
10.4
Blinding and unblinding
60
10.4.1
Methods of blinding
60
10.4.2
Methods of unblinding
60
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10.4.3
Identification of IMPs in emergency situations
60
10.5
Allowed and forbidden prior/concomitant medications or therapies
61
10.6
Documentation of drug accountability
61
11
COURSE OF THE TRIAL AND CONDITIONS
62
11.1
Course of the trial
62
11.1.1
Enrollment Period
62
11.1.2
Treatment Period A
63
11.1.3
Follow-up Period 1
67
11.1.4
Follow-up Period 2
70
11.2
Examination hierarchy and time windows
76
11.3
Conditions during the trial
76
11.3.1
Medical care
76
11.3.2
Meals and fluid intake restrictions
77
11.3.3
Dental hygiene
77
11.3.4
Counseling of women of reproductive age
77
11.4
Subject trial cards
77
11.5
Provisions of any additional care of subjects after trial termination
78
12
TRIAL ASSESSMENTS
78
12.1
Overview of blood sampling in this trial
78
12.2
Collection of demographic data and other baseline characteristics
79
12.2.1
Demographic data
79
12.2.2
Prior and concomitant medication or therapies
79
12.2.3
Relevant prior/concomitant disease or surgical interventions
79
12.2.4
Other baseline characteristics
81
12.3
Collection of efficacy data
81
12.3.1
Pain intensity
81
12.3.2
Dynamic mechanical allodynia
83
12.3.3
Pressure pain threshold
83
12.3.4
Edema measurement
84
12.3.5
Active range of motion measurement
84
12.3.6
CRPS Severity Score
84
12.3.7
Patient Global Impression of Change
85
12.3.8
Patient Global Impression of Severity
85
12.3.9
EuroQoL-5 dimension-5 level
85
12.3.10
PROMIS-29 profile and the PROMIS-EDDEP39
85
12.3.11
Short-Form McGill Pain Questionnaire 2: 6 neuropathic pain items
86
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12.3.12
Pain Catastrophizing Scale
86
12.3.13
Pain Self Efficacy Questionnaire
86
12.4
Collection of safety data
86
12.4.1
Adverse events
86
12.4.2
Vital signs
91
12.4.3
Body weight
91
12.4.4
Twelve-lead electrocardiogram
91
12.4.5
Safety laboratory
92
12.4.6
Physical examination
94
12.4.7
Urine beta-human chorionic gonadotropin pregnancy test
94
12.5
Collection of plasma concentration data
94
12.5.1
Blood sampling for bioanalysis
94
12.5.2
Bioanalytical assays
94
12.6
Collection of pharmacodynamic data
94
12.6.1
Bone turnover markers
94
12.7
Collection of markers for disease severity or progression of CRPS
95
12.7.1
Soluble interleukin-2 receptor (sIL-2R)
95
12.8
Collection of pharmacogenetic and omics data
95
12.9
Collection of health economics outcome and work productivity data (US 
sites only)
96
12.9.1
Work Productivity and Activity Impairment Questionnaire: CRPS
96
12.9.2
Medical resources utilization and health economics data collection
96
12.10
Appropriateness of measurements
96
12.11
Compliance
100
13
DOCUMENTATION OF TRIAL DATA
101
13.1
Case report forms
101
13.2
Subject-reported outcomes
101
13.3
External data
102
13.4
Data management
102
13.5
Source data
102
13.6
Investigator’s site file and the trial master file
103
14
QUANTITATIVE ANALYSES
103
14.1
Statistical methods and sample size determination
103
14.1.1
Sample size rationale
103
14.1.2
General description of statistical analyses
103
14.1.3
Analysis populations (analysis sets)
104
14.1.4
Subject disposition
104
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14.1.5
Analysis of demographic data and other baseline characteristics
104
14.1.6
Concomitant medication and therapies
104
14.1.7
Analysis of efficacy data
104
14.1.8
Analysis of safety data
107
14.1.9
Analysis of neridronic acid plasma concentration data
108
14.1.10
Analysis of pharmacodynamic data
108
14.1.11
Analysis of health economics outcome and work productivity data
109
14.1.12
Analysis of soluble interleukin-2 receptor
109
14.1.13
Interim analysis
109
14.2
Pharmacometric analyses
109
14.3
Analysis of the trial – pharmacogenetic and omics analysis
109
14.4
Ad hoc analyses
110
15
QUALITY SYSTEM, AUDIT, AND INSPECTION
110
15.1
Quality system
110
15.2
Data quality assurance
110
15.3
Inspections
110
16
GENERAL CONDITIONS AND AGREEMENTS
111
16.1
Insurance
111
16.2
Legal regulations
111
16.3
Contracts
111
16.4
Subject data and data protection
111
16.5
Public disclosure
112
16.6
Trial results reporting
112
16.7
Approval
112
16.7.1
Sponsor
112
16.7.2
Coordinating investigator
112
17
REFERENCES
112
18
APPENDIX
118
18.1
List of potentially important medical concepts – classified by System 
Organ Class
118
18.2
Algorithm for follow-up investigation of potential or suspected cases of 
drug-induced liver injury
121
18.3
Subject-reported outcomes
121
18.3.1
Patient Global Impression of Change
122
18.3.2
Patient Global Impression of Severity
123
18.3.3
EuroQol-5 dimension-5 level
124
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18.3.4
PROMIS-29 profile version 2.0
127
18.3.5
PROMIS-EDDEP39
130
18.3.6
Short-form McGill Pain Questionnaire 2: 6 neuropathic pain items
131
18.3.7
Pain Catastrophizing Scale
132
18.3.8
Pain Self Efficacy Questionnaire
133
18.3.9
Work Productivity and Activity Impairment Questionnaire: CRPS
135
18.4
Signs and symptoms of CRPS
136
18.5
Health Economics Outcome Questionnaire (sample)
137
19
PROTOCOL AMENDMENTS
163
19.1
Protocol Amendment 01
163
LIST OF IN-TEXT TABLES
Table 1:
Reasons for compulsory and optional discontinuation of subjects
54
Table 2:
Reasons for permanent and temporary discontinuation of subjects from 
IMP
55
Table 3:
Planned approximate blood sampling volumes collected from each 
subject
78
Table 4:
Complex regional pain syndrome clinical diagnostic criteria 
recommended by the IASP; “Budapest clinical criteria”
80
3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
3.1
Abbreviations
Abbreviation
Explanation
ß-HCG
Beta-human chorionic gonadotropin
ACR
Albumin to creatinine ratio
ANCOVA
Analysis of covariance
AROM
Active range of motion
BAP
Bone alkaline phosphatase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COMPACT
Core outcome measures for complex regional pain syndrome clinical trials
CRO
Contract research organization
eCRF
Electronic case report form
CRPS
Complex regional pain syndrome
CRPS-I/CRPS-II
Complex regional pain syndrome Type I/ Complex regional pain syndrome Type II
CTX
C-terminal telopeptide of type I collagen
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Abbreviation
Explanation
DMA
Dynamic mechanical allodynia
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EFPIA
European Federation of Pharmaceutical Industries and Associations
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EQ-5D-5L
EuroQoL-5 Dimension-5 level
FDA
Food and Drug Administration
GCP
Good clinical practice
IASP
International Association for the Study of Pain
IEC
Independent ethics committee
IL-2
Interleukin-2
IMMPACT
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
IMP
Investigational medicinal product
IRB
Institutional review board
MAR
Missing-at-random
MDMA
3,4-methylendioxy methamphetamine, ecstasy
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model for repeated measures
MNAR
Missing-not-at-random
NRS
Numerical rating scale
Omics
A generic term referring to analysis techniques like pharmacogenetics, genomics, 
epigenetics, transcriptomics, proteomics, metabolomics
PCS
Pain Catastrophizing Scale
PGIC
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PINP
Procollagen type I amino-terminal propeptide
PMI
Placebo multiple imputation
PMM
Pattern mixture model
PPT
Pressure pain threshold
PROMIS
Patient-Reported Outcomes Measurement Information System (PROMIS®)
PROMIS-29 profile
Patient-Reported Outcomes Measurement Information System (PROMIS®)-29 profile 
version 2.0
PROMIS-EDDEP39
Question EDDEP39 of the PROMIS Item Bank version 1.0 – Emotional Distress –
Depression
PSEQ
Pain Self Efficacy Questionnaire
QTcF
Corrected QT interval (according to Fridericia’s formula)
SAE
Serious adverse event
SF-MPQ-2
Short-Form McGill Pain Questionnaire 2
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Abbreviation
Explanation
sIL-2R
Soluble interleukin-2 receptor
SOP
Standard operating procedure (used as synonym for all procedural documents)
TEAE
Treatment emergent adverse event
USP
United States Pharmacopeia
VAS
Visual analog scale
WPAI
Work Productivity and Activity Impairment
Système International d’Unités units and standard hematological and biochemical abbreviations are not listed.
3.2
Definition of terms
Term
Definition
Allocated subjects
Enrolled subjects who are assigned to IMP.
Applicable regulatory 
requirement(s)
Any law(s) and regulation(s) addressing the conduct of clinical trials of IMPs of the 
jurisdiction where the trial is conducted.
CRPS Type I
Occurs after a minor or major tissue injury without clinical signs of major peripheral 
nerve injury.
CRPS Type II
Occurs after an injury with clinical signs of major peripheral nerve injury.
End of the trial
The trial-related end of the trial is defined as the date of last subject out. 
The subject-related end of trial is defined as date of last contact with the subject 
according to the protocol.
Enrolled subjects
Subjects who signed an informed consent form.
Enrollment failures
Enrolled subjects who were not allocated to IMP.
First subject allocated
First subject that was allocated to IMP.
First subject in
Date of first enrolled subject.
Investigational medicinal 
product
A generic term describing the preparation(s) under investigation in this trial, i.e., 
neridronic acid and placebo.
Last subject out
Date of last contact with the last subject according to the protocol.
Patient
Person under a physician’s care for a particular disease or condition.
Screened subjects
Screened subjects are subjects undergoing screening. Screening is any activity 
concerning subjects who could potentially be enrolled into the trial before the informed 
consent form is signed.
Subject
Individual who participates in a clinical trial (healthy person or patient), either as 
recipient of an IMP or as control.
Treated subjects
Subjects with at least 1 administration of IMP.
Use of the terms “must” and “should”
When “must” is used, the action/item is always mandatory. Non-compliance with this instruction 
constitutes a protocol deviation. 
When “should” is used, the action/item is recommended but not mandatory. Non-compliance with 
this instruction does not constitute a protocol deviation. 
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4
ETHICS
This trial will be conducted according to this protocol, the ethical principles that have their origin in 
the Declaration of Helsinki, good clinical practice (GCP), and applicable regulatory requirements.
This trial will be registered in public registries according to the applicable laws and requirements.
4.1
Independent ethics committees or institutional review boards
The relevant independent ethics committees (IECs) or institutional review boards (IRBs) for this 
trial will be provided with all documents required to fulfill their responsibilities. Any updates 
thereof will be provided according to GCP and applicable regulatory requirements.
Trial activities will only start when approval from the relevant IECs or IRBs is available.
Documentation of all involved IECs or IRBs will be maintained according to GCP and applicable 
regulatory requirements.
4.2
Subject information and informed consent
Before any trial-related procedure will be performed, freely given informed consent must be 
obtained.
The informed consent discussion, the information sheet (if used) and the informed consent form 
provided to subjects must adhere to GCP and applicable regulatory requirements. The informed 
consent discussion with the subject must be performed by the principal investigator or an 
appropriately trained delegate. The information sheet and informed consent form agreed with the 
sponsor must be used. Prior to use, these documents must be approved by the relevant IECs or 
IRBs.
Subjects must be informed as soon as possible if new information becomes available that may be 
relevant to their willingness to continue participation in the trial. The communication of this 
information must be documented.
Collection of blood samples for storage and pharmacogenetic and omics (a generic term referring to 
analysis techniques like pharmacogenetics, genomics, epigenetics, transcriptomics, proteomics, 
metabolomics) assessment is optional for trial subjects.
A separate informed consent for the collection of blood samples for pharmacogenetic and omics
testing will be obtained in addition to the standard informed consent for the clinical trial. Failure to 
provide this additional consent will not affect the subject’s ability to participate in the clinical trial.
A copy of the signed and dated informed consent form will be given to the subject and the original 
will be filed in the investigator’s site file.
Subjects who give consent for pharmacogenetic and omics testing may reconsider and decide to 
withdraw their consent. Subjects will be informed during informed consent that withdrawal of 
consent requires them to contact the investigator. The investigator will then notify the sponsor in 
writing of the subject’s decision, and the sponsor will instruct the bio-banking facility to destroy the 
stored sample(s) of the subject. The destruction of the subject’s sample(s) will be documented by 
the sponsor and in the bio-banking facility records. All pharmacogenetic and omics data already 
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evaluated prior to the withdrawal of consent will continue to be reported in completed or ongoing 
pharmacogenetic and omics analyses, but will be excluded from all subsequent analyses.
The subjects must be informed that any compound-related discoveries resulting from the 
pharmacogenetic and omics testing and analyses are the property of the sponsor. They may be used 
by the sponsor for commercial purposes.
4.3
Informing the subject’s healthcare provider
In countries where applicable, and only if the subject agrees in writing in the informed consent form 
and is treated by a healthcare provider, e.g., general practitioner, the subject’s healthcare provider 
should be informed about the subject’s participation in the trial at trial enrollment. The healthcare 
provider should be informed about the trial code, the principal investigator’s name, and a contact 
(telephone) number at the trial site. 
Any communication with the healthcare provider must be documented in the subject’s medical 
records or the investigator’s site file.
5
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
5.1
Investigators and trial site personnel
5.1.1
Investigators
There must be an investigator at each trial site.
If the trial is conducted by a team of individuals at the trial site, the investigator leading and 
responsible for the team is called the principal investigator.
All persons assigned responsibility as principal investigator must sign a declaration of their 
responsibilities and their agreement to this protocol before any trial-related procedure is performed.
Curriculum vitae and/or other relevant documents confirming the current qualification of the 
investigators must be provided to the sponsor. This should include any previous training in the 
principles of GCP, experience obtained from work with clinical trials, and experience with subject 
care.
Documentation of all involved investigators must be maintained according to GCP and applicable 
regulatory requirements.
In different countries, there may be country-specific terminology used for the investigator role.
An international coordinating investigator will be defined who is responsible for the coordination of 
principal investigators at multiple trial sites in multiple countries.
Documentation of all responsibilities assigned to the country-specific coordinating 
investigators/international coordinating investigator must be maintained according to GCP and 
applicable regulatory requirements.
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5.1.2
Trial site personnel assigned trial-related duties
The principal investigator may define appropriately qualified personnel at a trial site to perform 
significant trial-related procedures and/or to make trial-related decisions under his/her supervision. 
In this case, the principal investigator must maintain a signed list of the persons to whom they
delegate significant trial-related duties/responsibilities; the delegated trial-related 
duties/responsibilities must be specified in the list.
When personnel or responsibility changes are made, the principal investigator must ensure that the
relevant documentation is updated before any trial-related activities are performed. 
Documentation of all involved trial site personnel performing significant trial-related procedures 
and/or making trial-related decisions must be maintained according to GCP and applicable 
regulatory requirements.
5.2
Contract research organizations
Contract research organizations (CRO; commercial, academic or other, e.g., central laboratory 
facilities, trial supply management provider, electronic clinical outcomes assessment tool provider) 
may be contracted by the sponsor to perform trial-related duties and functions. The extent of the 
delegation must be documented. All involved CROs will be required to have implemented quality 
control and quality assurance processes, and to support the sponsor’s quality control and quality 
assurance measures.
Documentation of all involved CROs must be maintained according to GCP and applicable 
regulatory requirements. Documentation of any delegation of responsibilities to CROs must be 
maintained in the trial master file.
5.3
The sponsor and sponsor’s personnel
The trial sponsor listed on the title page accepts the responsibilities of the sponsor according to GCP 
and applicable regulatory requirements.
The sponsor must designate appropriately qualified personnel to advise on trial-related topics. The 
trial site will be provided with contact details for these personnel before any trial-related procedure 
is performed. 
A list of key sponsor personnel involved in the preparation of this protocol and the conduct of the 
trial, including their full names, titles, roles, and responsibilities, must be maintained.
A list of key personnel contracted by the sponsor and involved in the conduct of the trial including 
their full names, addresses, and responsibilities, must be maintained.
6
INTRODUCTION AND TRIAL BACKGROUND
6.1
Introduction
Complex regional pain syndrome is a severe and frequently chronic disabling condition that can 
develop after a minor injury, such as a fracture or sprain, usually in a distal extremity (hand, wrist, 
ankle, and foot). Complex regional pain syndrome is characterized by disproportionate pain, 
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relative to the inciting event, and signs and symptoms related to sensory, vasomotor and sudomotor 
abnormalities, trophic changes (abnormal skin, hair, and nails), and impaired motor function in the 
affected limb (Harden et al. 2010a). There are currently no Food and Drug Administration (FDA)
approved pharmacological treatments for CRPS, and patients are underserved due to a poor 
understanding of the pathophysiological processes and lack of evidence for effective treatments 
(Harden et al. 2013; Goebel 2013; Bruehl 2015). 
Randomized placebo-controlled trials of bisphosphonates in patients with CRPS suggest that these 
agents are efficacious for treatment of pain and other symptoms associated with this syndrome 
(Brunner et al. 2009; Cossins et al. 2013; O’Connell et al. 2013; Varenna et al. 2013; Wertli et al. 
2014). Since bisphosphonates act to suppress osteoclastic bone resorption, it is likely that bone 
pathology plays a role in the evolution and maintenance of CRPS Type I (CRPS-I; Gatti et al. 
2016), although other mechanisms may be involved (Varenna et al. 2013). Evidence of osteopenia 
and increased uptake of radiolabeled bisphosphonate tracer (observed during bone scintigraphy) in 
the affected limb(s) of patients with CRPS provides support for this hypothesis. Therefore, the 
present trial with a total dose of neridronic acid 400 mg is designed to obtain efficacy and safety
information to support the potential broader use of neridronic acid to address a major unmet 
medical need in patients with CRPS.
6.2
Background to the IMP
Neridronic acid is an alkyl-aminobisphosphonate with a chemical structure and potency similar to 
that of pamidronate (Gatti et al. 2013). Neridronic acid has been studied in subjects with Paget’s 
disease of bone, osteogenesis imperfecta, hypercalcemia, and osteoporosis and has been marketed 
in Italy under the tradename NERIXIA® for treatment of osteogenesis imperfecta since 2002 and 
for Paget’s disease since 2006. In 2014, NERIXIA received market authorization for treatment of 
CRPS in Italy.
Neridronic acid is currently being investigated for the treatment of CRPS.
6.3
Relevant non-clinical and clinical data
For a detailed summary of relevant non-clinical and clinical experience, see the current edition of 
the neridronic acid investigator’s brochure.
In a pilot trial of neridronic acid, 9 subjects with CRPS-I were randomized to 2, 3, or 4 infusions of 
100 mg intravenous neridronic acid every 4 days in the first phase of the trial (Varenna et al. 2004). 
The cumulative intravenous doses of 200 mg and 300 mg were considered suboptimally effective. 
The 4 x 100 mg dose of neridronic acid was identified as the only regimen providing clinical 
improvement equivalent to 300 mg/day intravenous clodronate for 10 days (i.e., a total dose of 
3000 mg) investigated in CRPS in an earlier trial (Varenna et al. 2000). Equivalence of the 400 mg 
cumulative dose of neridronate, based on indirect equivalence to 3000 mg clodronate, was 
confirmed in a second phase of the pilot trial with 18 patients.
In a multi-national, randomized, double-blind, placebo-controlled trial in patients with CRPS-I 
(KF7013 01; NCT02402530) total doses of 125 mg and 250 mg neridronic acid administered as 
4 intravenous infusions over a period of 10 days were well tolerated but did not differentiate 
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significantly from placebo on the primary efficacy parameter, confirming that a higher dose would 
be required for the effective treatment of CRPS.
In a multi-site, placebo-controlled trial of intravenous neridronic acid in 82 subjects with CRPS-I 
receiving 400 mg of neridronic acid, administered as four 2-hour infusions of 100 mg on Day 1, 
Day 4, Day 7, and Day 10, a statistically significantly greater percentage of subjects experienced at 
least 50% decrease in pain intensity at 40 days after the first infusion compared with placebo 
(73.2% for neridronic acid versus 32.5% for placebo [treatment difference: 40.7%; 95% confidence 
interval: 18.7%, 59.5%]; p = 0.0003). Secondary endpoints, including change from baseline in pain 
intensity, pain evoked by passive motion, edema, AROM, hyperalgesia, and allodynia, also showed 
significant improvements (Varenna et al. 2013). There were no serious or severe adverse events in 
the neridronic acid treatment group. The most frequent adverse events were arthralgia, fever, and 
headache, consistent with the acute phase reaction.
6.4
Trial rationale
Grünenthal is currently developing intravenous neridronic acid for treatment of CRPS.
The aim of the current trial is to investigate the efficacy, safety, and tolerability of neridronic acid 
administered as 4 intravenous infusions of neridronic acid 100 mg, resulting in a total dose of 
400 mg, in subjects with CRPS. This pivotal trial is intended to be an integral part of the overall 
efficacy and safety assessment of neridronic acid for the treatment of subjects with CRPS and to 
support product registration.
Additional aims are to assess the safety and tolerability of initial dosing with neridronic acid for up 
to 12 months, to assess the need for further treatment after 6 months, and to describe the effect of an 
additional treatment cycle of 4 additional infusions of 100 mg of neridronic acid.
7
TRIAL OBJECTIVES AND ENDPOINTS
The trial objectives and endpoints are given in Section 1.2.
The pain intensity score used for the primary endpoint will be calculated from average pain 
intensity ratings, assessed once daily in the electronic diary and referring to the CRPS-affected 
limb. The baseline average pain intensity score is defined as the average of the week before 
allocation to treatment at Visit 2 and calculated as the average of the 7 average pain intensity ratings 
starting in the evening of Day -7 until Day -1. A baseline pain intensity score (∀4 on the NRS) must 
be confirmed at the site prior to subject allocation (at Visit 2). Subjects who do not meet eligibility 
criteria due to inadequate pain (<4 on the NRS) will be excluded from the trial.
Pain intensity scores from Week 1 through Week 12 will be calculated in a similar manner using 
average pain intensity ratings obtained from the electronic diary. The Week 12 pain intensity score, 
for evaluation of the primary outcome, will be the average of up to 7 possible ratings obtained in the 
7-day period culminating with the rating obtained in the evening prior to the Week 12 visit. 
Handling of missing pain ratings will be addressed in the statistical analysis plan. Compliance with 
the pain ratings in the electronic diary must be monitored and subjects with insufficient ratings 
(<4 ratings per week for 2 weeks) should receive a reminder and undergo re-training.
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During Visit 2 (Day 1), Visit 7 (Week 6), Visit 8 (Week 12), Visit 9 (Week 16), and Visit 11
(Week 26), Visit 16 (Week 36), and Visit 17 (Week 52), the subjects will be asked to record the 
pain intensity ratings for average, worst, and current CRPS-related pain directly on a tablet 
computer maintained at the site. For subjects included in Treatment Period B, the subjects will also 
be asked to record pain intensity rating at Visit 12, Visit 13, Visit 14, and Visit 15. Worst and 
average pain intensity ratings will be based on a 24-hour recall period. The pain ratings and other 
patient-reported outcomes from the tablet computers recorded up to Week 26 as well as DMA, 
edema, and PPT assessment will be used for the secondary endpoints.
8
TRIAL DESIGN
8.1
Discussion of the trial design
This is a multi-site, randomized, double-blind, placebo-controlled, 2-arm, Phase III trial of 
intravenous neridronic acid in subjects with CRPS.
The trial design was selected to confirm the efficacy and safety of neridronic acid in subjects with 
CRPS. A randomized, double-blind design was chosen to avoid selection bias and provide balance 
of baseline characteristics across treatment groups. Blinding is critical to minimize potential biases 
resulting from differences in management, treatment, or assessment of subjects, or interpretation of 
results that could arise as a result of subject or investigator knowledge of the assigned treatment.
Parallel-group designs are well-understood from a statistical design perspective. A crossover, 
randomized-withdrawal, or other design was considered unsuitable for this trial due to the very long 
half-life of bisphosphonates, which may persist in bone for years.
The 11-point NRS is a standard, widely used tool for the assessment of pain and is recommended 
by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) as 
a core outcome measure in chronic pain trials (Dworkin et al. 2005).
The efficacy assessments chosen for this trial reflect the core outcome measures for CRPS clinical 
trials (COMPACT; Grieve et al. 2017). For further details, see Section 12.10.
Semi-objective measures for frequent signs of CRPS beyond spontaneous pain (i.e., DMA, PPT 
edema, AROM) have also been included.
Choice of control
Use of a placebo control is considered justifiable when there are no established effective treatments 
for a disease or condition (ICH E10). As reflected in a recent Cochrane review of interventions for 
CRPS, there is no consensus for optimal management of this condition and the limited number of 
published trials provides only low or very low quality of clinical evidence for any intervention 
(O’Connell et al. 2013). In the absence of a suitable active comparator, the use of a placebo control 
allows for blinding and randomization to control for expectations of benefits that may occur from 
being in the trial. The placebo group also controls for spontaneous changes in the course of the 
disease. The use of placebo in this trial does not imply that subjects will be untreated, as subjects 
may continue to receive stable analgesic regimens during the trial as well as short-acting analgesics 
in case of severe pain flare related to CRPS (for details, see Section 1.4.2).
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Trial design limitations
The concomitant use of pain medications in this trial, which are allowed because of the severity of 
the condition, may affect the sensitivity of subject-reported outcomes and the ability to detect 
changes in pain intensity. Therefore, it is important to emphasize the need for stable treatment 
during the trial at least until Week 12 to optimize assessment of the primary endpoint. Any changes 
in pain medications must be recorded.
Second treatment course
For those subjects not experiencing sufficient efficacy after a first treatment course with IMP as 
assessed at Visit 11 (Week 26), a second treatment period (Treatment Period B) in subjects with 
persistent pain is included to allow subjects previously on neridronic acid and on placebo to be 
treated with neridronic acid either for the second or the first time, respectively. The second 
treatment course is scheduled to occur after 26 weeks.
Subjects treated during Treatment Period B will provide data on safety and tolerability of a second 
treatment course as well as descriptive data on the efficacy of a second treatment course in subjects 
with no or insufficient response to the first treatment course as well as in subjects who lost response 
to the initial treatment course. Furthermore, subjects from the placebo group can receive verum 
treatment in Treatment Period B.
8.1.1
Rationale for the trial population
Although previous trials with neridronic acid have been performed in subjects with CRPS-I, 
CRPS-I and CRPS Type II (CRPS-II) are likely to share the same pathophysiological basis 
(Oaklander and Horowitz 2015; Bruehl 2015).
There are no known methods to objectively distinguish between CRPS-I and CRPS-II subtypes, as 
electromyography and nerve conduction studies have low negative predictive value and do not rule 
out nerve abnormalities in CRPS-I. Furthermore, pathophysiological changes in bone, the principal 
target for efficacy of neridronic acid, may occur in patients diagnosed with CRPS-II.
Given the uncertain distinctions between these subtypes and lack of pathologic or pharmacologic 
basis for restricting treatment to CRPS-I, subjects with CRPS-II will also be included in this trial.
Reports from the literature suggest better responses to treatment when subjects are treated early 
after onset of the first symptoms (Wertli et al. 2014). There is no consensus on an exact time 
window for treatment. Preliminary data from an open-label trial employing a cumulative dose of 
neridronic acid 400 mg (KF7013-03), suggest clinically relevant decreases in pain intensity in a 
subgroup of subjects with a CRPS duration ≤2 years. The trial population in this trial will therefore 
be limited to this disease duration.
Subjects must be on stable therapy prescribed for CRPS for at least 1 month prior to randomization 
and allocation to maximize sensitivity to detect changes in pain intensity and other efficacy 
outcomes. Analgesic regimens including pro re nata (as needed) opioids or other analgesics are 
allowed if the regimen has been prescribed as part of a stable treatment. The investigator must 
select subjects who are anticipated to be able to maintain a stable treatment regimen for the first 
12 weeks of the trial (up to and including Visit 8). Initiation of new therapies during the trial will be 
prohibited. Short courses of analgesics, including opioids (unless prohibited according to 
Section 1.4.2.1), will be allowed to be prescribed in the event of a severe pain flare.
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8.1.2
Rationale for the investigational medicinal products and the selected 
doses
A previous pilot trial of neridronic acid, including cumulative intravenous doses of 200 mg, 
300 mg, and 400 mg, suggested that doses below 400 mg were suboptimally effective (Varenna et 
al. 2004).
A previous randomized, double-blind, placebo-controlled trial performed by Abiogen Pharma 
S.p.A. demonstrated that a 400 mg cumulative intravenous dose of neridronic acid is effective, safe, 
and well tolerated in subjects with CRPS-I (Varenna et al. 2013; Clinical Study Report 
NERI-AS001-07). As the 4 x 100 mg dose regimen used in that trial has been approved for 
treatment of CRPS-I in Italy, the same dose regimen was selected for investigation in this trial.
In Italy, the recommended infusion time for 100 mg neridronic acid to treat osteogenesis imperfecta 
and CRPS-I is 2 hours. To limit the maximum concentrations (Cmax) in this trial to levels similar to 
(and unlikely to exceed) those obtained in the KF7013-01 trial, in which 62.5 mg neridronic acid 
was infused in 2 hours, the infusion time has been extended to 4 hours.
8.1.3
Rationale for the number and the frequency of visits/assessments
The number and frequency of visits are considered to be sufficient to ensure subject safety and meet 
trial objectives.
8.1.4
Background and rationale regarding pharmacogenetic and omics testing
The European Medicines Agency (EMA; 2011) and United States FDA (2013) guidance documents 
recommend the conduct of pharmacogenetic assessments in clinical trials during drug development 
(Phase I to Phase III).
Genetic factors are suggested to play a role in CRPS (de Rooij et al. 2009). To further characterize 
protein-coding areas, signatures, and haplotypes related to CRPS-I, potentially relevant genes 
together with genes of the corresponding signaling pathways will be analyzed using genotyping of a
panel of pre-selected single-nucleotide polymorphisms and proteomics of proteins encoded by these 
genes. The aim is to identify relevant pathways and gene-phenotype associations that will allow a 
phenotypic characterization of CRPS pain conditions. The associated single-nucleotide 
polymorphisms will be related to all corresponding proteins and then further analyzed using omics
methods to identify potential biomarkers. In addition, the associated single-nucleotide 
polymorphisms will be used to identify potential genetic predispositions to CRPS and the function 
of these genes in response to treatment and disease progression, including potential linked side 
effects.
All measurements and analyses will be described in separate pharmacogenetic and omics plans.
8.2
Benefit/risk analysis
Potential benefits to subjects participating in this trial may include a reduction in pain and other 
symptoms of CRPS, as well as benefits of medical supervision from being in a clinical trial.
Risks to subjects participating in this trial are primarily related to the known side effects of 
neridronic acid and bisphosphonates as a class, particularly those associated with intravenous 
administration. Although doses of up to 400 mg of neridronic acid have been administered safely in 
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subjects with Paget’s disease or CRPS-I, most of the clinical experience for neridronic acid has 
been at doses of 200 mg or below. In addition to drug-specific risks, there are also the risks of the 
procedures used in the trial.
In order to minimize the risk for the subject, it is obligatory that the investigator becomes familiar 
with all sections of the current neridronic acid investigator’s brochure prior to the initiation of the 
trial and follows the warnings and directions thereof.
The trial population described in this protocol will consist of subjects with a diagnosis of CRPS, 
with onset of symptoms within the last 2 years, and who are medically stable and in stable follow-
up therapy for CRPS for at least 1 month prior to allocation.
Subjects will continue to receive stable therapy for CRPS. Additional pain medication may be 
prescribed in the event of severe pain flare, with notification of the sponsor or sponsor’s 
representative (i.e., medical monitor). Changes in analgesic medications and other treatments for 
CRPS may be permitted after Week 12, following notification of the sponsor or sponsor’s 
representative (i.e., medical monitor). After Visit 10, investigators will assess the further need of 
concomitant treatment for CRPS, in particular opioids, and evaluate if the dose or frequency of 
these treatments can be decreased, or if treatment can be stopped completely. This will help to 
ensure that subjects in the trial will not suffer from untreated pain and that the subject’s exposure to 
other analgesics will be decreased or stopped if they are no longer needed. Subjects may withdraw 
from the trial at any time, without giving a reason and without prejudice. However, subjects who 
withdraw will be asked to continue follow-up visits if at all possible for the scientific integrity of 
the trial as well as for their own safety.
Potential risks and risk management of neridronic acid
Acute phase reaction
The most common side effects associated with parenteral administration of aminobisphosphonates 
are flu-like symptoms, commonly referred to as “acute phase reaction” (Reid et al. 2010; Silverman 
et al. 2011). Symptoms include fever, myalgia, fatigue, headache, diarrhea, arthralgia, and bone 
pain. These are self-limiting and usually resolve after 24 hours to 48 hours. Symptoms of the acute 
phase reaction typically occur following the first administration and are absent or decreased 
following subsequent administrations. For symptomatic management of the acute phase reaction, 
oral acetaminophen (paracetamol) is recommended (for details, see Section 1.4.2). Non-steroidal 
anti-inflammatory drugs should not be used to alleviate the symptoms of the acute phase reaction 
due to their potential to cause acute changes in renal function, which may confound renal safety 
assessments.
Ocular effects
Eye disorders have been reported with neridronic acid and appear to be associated with the acute 
phase reaction. These events include anterior uveitis, episcleritis, conjunctivitis and ocular pain. As 
severe ocular inflammation may increase the potential risk of long-term vision loss, treatment with 
neridronic acid will be discontinued at first signs of ocular inflammation, followed by an 
ophthalmologic exam.
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Hypocalcemia
Aminobisphosphonates are potent inhibitors of bone turnover, and are thus associated with a risk of 
hypocalcemia.
The normal compensatory mechanism is an increase in parathyroid hormone, which can trigger 
renal absorption of calcium and vitamin D3 production in response to a decreased calcium efflux 
from the skeleton after bisphosphonate therapy (Polyzos et al. 2011).
Subjects with abnormal blood calcium or magnesium concentrations, a history of disorders that 
impair the compensatory increase in parathyroid hormone, or concomitant use of any drug with 
known potential to cause hypocalcemia will be excluded from the trial. Retesting of out-of-range 
values is permitted once during the Enrollment Period. Albumin-corrected serum calcium should be 
considered when serum albumin is below the normal range (e.g., <3.5 g/dL).
All subjects will be provided with supplemental calcium and vitamin D, starting from Visit 1 and 
continuing through to the end of the trial (for details, see Section 1.4.2). Subjects with vitamin D 
levels below 30 ng/mL (75 nmol/L) will receive supplementation to achieve values of at least 
30 ng/mL (75 nmol/L) prior to allocation to IMP. Subjects who do not reach vitamin D levels of at 
least 30 ng/mL (75 nmol/L) following appropriate supplementation will be excluded from the trial.
Renal toxicity
Based on the available data for neridronic acid, there is no clinical evidence for renal safety 
concerns to date. Nevertheless, renal toxicity was observed in non-clinical studies of neridronic acid 
and is regarded as a class effect of intravenous bisphosphonates. In most cases, signs for renal 
toxicity following administration of other intravenous bisphosphonates were transient and reversible 
after discontinuation of the drug or dose adjustment. Pronounced renal toxicity is a rare event, more 
common in long-term use, and there is a contributing role of pre-existing renal disease as well as 
other factors like other medication associated with renal toxicity and dehydration.
Bisphosphonates are rapidly cleared by the kidneys, potentially leading to a high concentration in 
kidney tissue during and immediately after the infusion. Dose and infusion time are the main factors 
related to renal toxicity.
In order to mitigate the risk of renal toxicity, subjects with evidence of severe renal impairment will 
be excluded (for details, see exclusion criterion 1).
Taking into account that renal toxicity due to intravenous bisphosphonates is related to the 
maximum drug concentration achieved and not the area under the curve of drug exposure (Khosla et 
al. 2012), 400 mg neridronic acid will be administered as 4 infusions of 100 mg neridronic acid 
administered over 240 minutes at Visit 2, Visit 3, Visit 4, and Visit 5 (and Visit 11, Visit 12, 
Visit 13, and Visit 14 during Treatment Period B) to subjects with no or mild renal impairment.
For subjects with moderate renal impairment, the dose will be adjusted (see Section 10.2). 
Due to the potential for renal toxicity with neridronic acid as with other bisphosphonates, renal 
safety monitoring will be implemented in this trial together with defined stopping criteria (for 
details, see Section 9.3.2).
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Cardiovascular
Despite the ability to transiently lower calcium levels, there has been no indication to date that 
bisphosphonates, as a class, cause prolongation of QT interval. Neridronic acid has not been studied 
in dedicated safety trials to evaluate a potential effect on the QT interval. Subjects with risk factors 
for QT prolongation or cardiac arrhythmia, including abnormal serum potassium levels, are 
excluded from this trial. Subjects will undergo regular 12-lead ECG examinations throughout the 
trial.
Medication-related osteonecrosis of the jaw
Osteonecrosis of the jaw is a rare adverse effect of bisphosphonate therapy, most commonly 
reported for patients with multiple myeloma and osteolytic bone metastases receiving repeated 
monthly infusions for treatment of skeletal related events and bone pain. Factors that may 
contribute to risk of osteonecrosis of the jaw include recent tooth extraction, unhealed or infected 
extraction sites, dental/periodontal disease, improperly fitting dentures causing injury, and prior 
radiation of the head or neck.
Invasive dental procedures should be avoided during the trial; however, subjects who require 
emergency dental surgery during the trial should proceed with appropriate treatment including 
prophylactic antibiotics and frequent follow-up. Subjects should be encouraged to use good dental 
hygiene (daily flossing and gentle brushing) throughout the trial.
Osteonecrosis of the external auditory canal 
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in 
association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory 
canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. 
The possibility of osteonecrosis of the external auditory canal should be considered in patients 
receiving bisphosphonates who present with ear symptoms including chronic ear infections and/or 
local risk factors such as infection or trauma.
Atypical femoral fractures
Although a causal relationship has not been conclusively established, meta-analysis suggests there 
is an increased risk of atypical femoral fractures in long-term bisphosphonate users. These fractures 
have a low prevalence (1.1% of all femoral fractures), and the absolute risk to patients receiving
bisphosphonates is low. Subjects should be advised to report any thigh, hip, or groin pain, and any 
patient who develops these symptoms should be evaluated for the presence of an incomplete femur 
fracture.
Other effects on bone
Although the potential for deleterious effects on bone following long-term treatment with 
bisphosphonates remains controversial to this day, no histomorphometric evidence of osteomalacia 
was reported at doses up to neridronic acid 250 mg in patients with Paget’s disease of bone 
(McCloskey et al. 1987; Atkins et al. 1987), in contrast to findings following administration of the 
first generation bisphosphonate, etidronic acid.
Supporting the absence of any important effect on bone health, long-term neridronic acid treatment 
increased bone mineral density and lowered risk of clinical fracture in children and adults with 
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osteogenesis imperfecta. These results argue against a deleterious effect on bone mineralization due 
to neridronic acid.
However, the potential for deleterious effects of bisphosphonates on bone has been suggested in 
conditions of low bone turnover, such as renal osteodystrophy or other adynamic bone disease, 
although the benefit/risk profile in these conditions is unclear. In addition to exclusion of subjects 
with chronic kidney disease stage 4 and 5, subjects with known defects in bone mineralization or 
adynamic bone disease are excluded from the trial.
Pregnancy and breastfeeding
There are no adequate and well-controlled trials of neridronic acid in pregnant or lactating women. 
Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, 
and animal data suggest that uptake of bisphosphonates into fetal bone may be greater than into 
maternal bone. Therefore, neridronic acid should not be administered during pregnancy and 
lactation and as a result, pregnant or lactating women are excluded from participation in this trial.
Women of child-bearing potential must have a negative urine β-HCG pregnancy test at the 
Enrollment Visit and prior to each infusion of IMP. Trial subjects must use contraception as defined 
in inclusion criterion 6.
Risks related to acetaminophen and calcium and vitamin D supplementation
High doses of acetaminophen may cause hepatotoxicity and can lead to liver failure. Subjects who 
take acetaminophen for prevention or relief of symptoms of the acute phase reaction during the 
treatment periods will be reminded that the total dose must not exceed 4 g/day and that caution 
should be exercised since acetaminophen may be present in many over-the-counter drugs, 
particularly analgesic medications.
Recommended daily doses of calcium and vitamin D are lower than the tolerable upper intake level, 
at which there is no risk to healthy individuals (Ross et al. 2011; Rosen et al. 2012). Short courses 
of high doses of vitamin D are anticipated to pose no significant risk to trial participants.
General risks
Subjects will be regularly monitored for any changes in their medical status, e.g., vital signs, ECG 
parameters, and laboratory values, during the trial (see Section 12.1 for overall volume of blood 
samples).
Blood sampling may cause pain or bruise at the site where the blood is taken due to insertion of the 
needle. No other invasive procedure is planned. The total volume of blood to be collected and the 
planned sampling frequency do not pose any clear risk and are considered justifiable in the context 
of the trial and its duration.
Conclusion
As there are currently no FDA or EMA approvals for specific pharmacological treatments for 
CRPS, which is a severe pain condition with limited effective treatment options, the potential for 
benefit of neridronic acid is considered to outweigh the potential risk in this population. The need 
for controlled efficacy and safety trials of potential new treatments for CRPS justifies this trial on 
moral and ethical grounds.
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9
SUBJECT ENROLLMENT AND TRIAL DISCONTINUATION
9.1
Subject enrollment procedure
Subjects will be screened to identify subjects who could potentially be enrolled into the trial. 
Potentially eligible subjects will be asked to enroll into the trial by giving written informed consent.
If required by applicable regulatory requirements, the (principal) investigator must keep suitable 
logs of the subject enrollment procedure.
Subjects who were enrolled in KF7013-01 but were not allocated to treatment (i.e., did not receive 
any treatment with IMP) or who only received placebo may be eligible if they satisfy all inclusion 
and exclusion criteria in Section 1.3.
Re-enrollment will be permitted (once), upon approval by the sponsor, for subjects with technical 
reasons for enrollment failure (e.g., inadequate time period for stabilization of treatment; inadequate 
time from discontinuation of a prohibited medication or treatment). No subject who received 
infusion of IMP, even a partial infusion, is allowed to be re-enrolled. Re-enrollment of subjects who 
did not meet inclusion criteria related to the diagnosis of CRPS and the baseline pain level is not 
allowed. Re-enrolled subjects must fulfill all inclusion and exclusion criteria in the current protocol. 
If a subject is re-enrolled, a new subject ID will be assigned and all enrollment procedures will be 
performed under the new subject ID.
9.2
Inclusion/exclusion criteria
The trial population must comply with the inclusion/exclusion criteria given in Section 1.3.
Subjects will only receive IMP if documentation is available showing that they comply with all of 
these criteria.
9.3
Subject discontinuation from the trial or IMP
Once a subject enrolls in this trial, whilst protecting subject safety, the trial site should make every 
effort to retain the subject for the planned duration of the trial.
A subject may withdraw consent at any time.
9.3.1
Subject discontinuation from the trial
All bisphosphonates have a long retention time in bone, and duration of efficacy is related to their 
persistent effects on bone turnover, specifically the inhibition of activation of bone resorption (Al 
Nofal et al. 2015; Naylor and Eastell 2012; Jung and Lein 2014). Collection of follow-up data is 
important for characterizing the safety and efficacy of neridronic acid. Subjects who receive any 
treatment, even a partial infusion, should be encouraged to remain in the trial for the full duration 
for follow-up safety and efficacy assessments.
Under certain situations, discontinuation from the trial may be required or be in the best interest of 
the subject from a risk/benefit perspective. Table 1 lists mandatory and optional reasons for 
discontinuation from the trial.
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Table 1:
Reasons for compulsory and optional discontinuation of subjects
Reason
Discontinuation from trial
Compulsory
Optional
Enrollment failure (i.e., subject was not allocated to treatment due to 
failure to meet inclusion or exclusion criteria and did not receive IMP).
X
Subject withdrawal of consent (the reason for withdrawal must be 
specified).
X
Subject death.
X
Subject loss to follow-up (i.e., no further contact with the subject is 
possible).
X
Sponsor decision to discontinue the subject.
X
Technical reasons (e.g., site is no longer able to function or participate in 
the trial, and the subject is too remote from other site locations).
X
Sponsor decision to terminate the trial.
X
Other reasons (e.g., subject becomes engaged in litigation related to their 
disability from CRPS in which monetary gain may affect their objective 
participation in the trial).
X
CRPS = complex regional pain syndrome, IMP = investigational medicinal product.
9.3.2
Subject discontinuation from the IMP
Discontinuation of IMP applies only to Treatment Period A or Treatment Period B. Subjects who 
are discontinued from IMP should not be discontinued from the trial except for reasons indicated in 
Table 1. Subjects who are discontinued from IMP should be encouraged to remain in the trial for 
their own safety and for the integrity of the trial.
Subjects must be evaluated prior to each infusion of IMP. The investigator must permanently or 
temporarily discontinue treatment with IMP for any reasons listed in Table 2. The investigator may 
decide to temporarily discontinue a subject from receiving IMP for other reasons (e.g., if further 
assessments may be helpful to assure safety of the subject). The investigator may also choose to 
permanently discontinue a subject from treatment if they believe that continued exposure of the 
subject to neridronic acid may pose an undue risk to the subject, e.g., due to particular adverse 
events or due to deterioration in the subject’s health for reasons related or unrelated to the 
treatment. 
In situations where treatment is temporarily discontinued, Treatment Period A or Treatment 
Period B may be extended to a maximum of 21 days (for details, see footnote b) in Section 1.7.1
and Section 1.7.2).
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Table 2:
Reasons for permanent and temporary discontinuation of subjects from IMP 
Discontinuation from IMP
Reason
Permanent
Temporary
Symptomatic hypocalcemia.
X
Serum calcium <7.8 mg/dL (<1.95 mmol/L). The subject may resume 
treatment following investigator assessment and a repeat serum calcium 
value above this limit (albumin-corrected serum calcium should be 
considered if serum albumin is below 3.5 g/dL).
X
Clinical signs of dehydration (e.g., dizziness, palpitations, confusion).
X
Test results suggestive of a possible change in renal function:
•
A persistent ∀25% decrease in the eGFR from the last value 
observed prior to the first IMP administration, based on 
repeated central laboratory results from blood samples obtained 
at least 1 week apart a.
X
•
A ∀25% decrease in the eGFR from the last value observed 
prior to the first IMP administration. If a repeated measurement 
of eGFR is within 75% or more of the respective value, the 
subject may resume treatment a.
X
•
A persistent urinary ACR based on an initial value >300 mg/g 
(semi-quantitative dipstick or quantitative urinary albumin and 
creatinine data from the central laboratory) and on a second 
value ≥150 mg/g (quantitative urinary albumin and creatinine 
data from the central laboratory) from urine samples obtained at 
least 1 week apart.
X
•
A urinary ACR >300 mg/g based on the results of the semi-
quantitative dipstick or quantitative data from the central 
laboratory. The subject may resume treatment if quantitative 
urinary albumin and creatinine data from the central laboratory 
indicate a urinary ACR value <150 mg/g from urine samples 
obtained at least 1 week apart.
X
•
A persistent eGFR <30 mL/min/1.73 m2 based on repeated 
quantitative data from the central laboratory, with urine samples 
obtained at least 1 week apart.
X
•
An eGFR <30 mL/min/1.73 m2. If a repeated measurement of 
eGFR is ∀30 mL/min/1.73 m2, the subject may resume 
treatment.
X
An average QTcF interval of >500 ms based on triplicate ECGs, or 
average QTcF interval of >480 ms with a concurrent increase in average 
QTcF interval >60 ms relative to the average of triplicate ECGs obtained 
at Visit 1.
X
Pregnancy.
X
Development of hypersensitivity to the IMP.
X
Signs or symptoms of ocular inflammation: b 
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Discontinuation from IMP
Reason
Permanent
Temporary
•
Resolution of signs and symptoms within 5 days.
X
•
Persistent or recurrent signs and symptoms.
X
Newly occurring risk factors for osteonecrosis of the jaw (e.g., need for 
emergency dental surgery).
X
Any other adverse event causing a significant deterioration in subject’s 
health.
X
Major protocol deviations (e.g., serious non-compliance with protocol 
procedures, unsafe use of forbidden medication, abuse of illicit drugs, or 
other reckless behavior during the trial that may jeopardize the subject’s 
safety or safety of other subjects or site staff).
X
a) Not applicable if no eGFR value after first IMP administration is available. For both treatment periods, the last value 
observed prior to first IMP application in Treatment Period A will be used for calculating the decrease in eGFR.
b) Subjects should be assessed for ocular inflammation by the investigator prior to each infusion (signs and symptoms 
include eye redness and irritation, blurred vision, eye pain, and sensitivity to light). Subjects with signs or symptoms of 
ocular inflammation should be temporarily suspended from treatment. Subjects with resolution of signs and symptoms 
within 5 days may resume treatment. Subjects with persistent or recurrent signs and symptoms of ocular inflammation 
must be discontinued from IMP and undergo an ophthalmologic examination.
ACR = albumin to creatinine ratio, eGFR = estimated glomerular filtration rate, ECG = electrocardiogram, 
IMP = investigational medicinal product, QTcF = corrected QT interval (according to Fridericia’s formula).
9.3.3
Procedure for the handling of discontinued subjects
9.3.3.1
Handling of subjects who discontinued from the trial
The principal investigator must document any discontinuation of a subject and inform the sponsor. 
Where applicable, the relevant IECs or IRBs must be informed with a detailed written explanation.
The following must be done for all discontinued subjects, including those who withdrew informed 
consent:
•
Document the main reason for discontinuation from the trial.
•
Ensure that all data collected until the time of discontinuation is transferred to the eCRF.
•
Complete any other trial-related formalities, e.g., those related to discharge from the trial 
site.
•
For subjects withdrawing consent, document in the source data the date and time of 
withdrawal.
•
If possible, perform an Early Termination Visit, with procedures identical to Visit 17. 
Subjects who withdraw consent and agree to perform the Early Termination Visit must 
document their approval in writing.
9.3.3.2
Handling of subjects discontinued from the IMP but not from the trial
Subjects who are temporarily suspended from IMP may undergo abbreviated visits for safety 
assessments to support a decision to continue treatment or permanently discontinue IMP. Subjects 
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who are permanently discontinued from IMP should proceed to Visit 6 (for Treatment Period A) or 
Visit 15 (for Treatment Period B) at approximately 4 days after the last infusion, if possible; Visit 7
or Visit 16, respectively, and subsequent visits will proceed according to the original visit schedule 
(relative to Visit 2).
9.3.3.3
Replacement of subjects
Subjects will not be replaced.
9.3.4
Premature termination or suspension of the trial
The following criteria for premature termination or suspension of the trial apply:
•
Significant changes in the risk-benefit profile assessment, based on emerging safety or 
efficacy information, such that continuation of the trial would compromise ethical treatment 
of subjects within or outside of the trial.
•
Request for termination or suspension of the trial by the FDA or other regulatory agency.
•
Decision by the sponsor to terminate the program.
The sponsor also reserves the right to close an investigational site, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. Reasons for early 
closure of an investigational site include failure of the investigator to comply with the protocol, 
sponsor’s procedures, or GCP guidelines; inadequate recruitment of subjects by the investigator; 
and enrollment target reached.
The relevant IECs or IRBs, the regulatory authorities, or the sponsor or the sponsor’s authorized 
delegate alone or in conjunction have the power to make a binding decision to prematurely 
terminate or suspend the trial at any or all trial sites. In addition, for an individual trial site, this 
decision can be made by the principal investigator.
The party prematurely terminating or suspending the trial must promptly inform all other parties 
(i.e., the principal investigators, the relevant IECs or IRBs, the relevant regulatory authorities, or the 
sponsor/the sponsor’s authorized delegate, as applicable).
In addition, if the principal investigator decides to terminate or suspend the trial at the trial site, they
must promptly inform the subjects, ensure appropriate follow-up for any enrolled subjects, and 
provide the relevant IECs or IRBs and the sponsor or the sponsor’s authorized delegate, as 
applicable, with a written explanation of the termination or suspension.
The international coordinating investigator and country-specific coordinating investigators must be 
informed immediately if the trial is prematurely terminated or suspended.
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10
TRIAL TREATMENTS
10.1
Investigational medicinal products
10.1.1
Identity and composition – neridronic acid
Name:
Sodium neridronate hemi hydrate for intravenous infusion.
Active component:
Neridronic acid.
Dose (strength):
Sodium neridronate hemi hydrate 108 mg for intravenous infusion 
(equivalent to 100 mg neridronic acid) supplied in 8 mL of excipients.
Supplier:
Grünenthal GmbH, Aachen, Germany.
10.1.2
Identity and composition – matching placebo
Name:
Placebo matching sodium neridronate hemi hydrate for intravenous 
infusion.
Active component:
Not applicable.
Dose (strength):
Not applicable.
Supplier:
Grünenthal GmbH, Aachen, Germany.
For further information about the identity and composition of the IMPs, see the investigator’s 
brochure and the clinical supply specification (available on request).
10.1.3
Preparation
The IMP is supplied in glass vials, each containing 108 mg sodium neridronate hemi hydrate 
(equivalent to 100 mg neridronic acid) or matching placebo in a total volume of 8 mL.
Instructions will be provided for the proper handling of vials.
The IMP will be prepared and infused by appropriately trained personnel at the trial sites.
For each infusion, before use, the IMP must be diluted in sterile normal saline (0.9% NaCl, e.g., 
United States Pharmacopeia (USP) grade saline for injection) to a volume of approximately 
500 mL. For subjects with moderate renal impairment, the respective reduced volume of IMP will 
be used (see Section 10.2). The IMP should not be diluted in solutions containing calcium and 
should not be infused in combination with any other medication. The volume of IMP transferred to 
the infusion bag must be recorded in the eCRF.
10.1.4
Packaging and labeling
For detailed information about the packaging and labeling, see the clinical supply specification 
(available on request).
10.1.5
Delivery, storage, and disposal
For detailed information about the distribution of the IMP, see the clinical distribution specification 
(available on request).
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At the investigator’s site, the IMPs must be stored in a secure and temperature controlled room with 
restricted access and temperature monitoring and must not be stored above 30°C.
The medication must not be frozen or refrigerated in order to maintain the quality of the packaging 
and labeling.
Controls will be implemented at the trial site to ensure documented compliance with these 
requirements.
10.2
Administration of investigational medicinal products
For subjects with no or mild renal impairment, the full contents of a single vial (8 mL) will be 
diluted in 500 mL normal saline and administered by slow intravenous infusion (240 minutes 
[maximum 260 minutes]) at Visit 2, Visit 3, Visit 4, and Visit 5, resulting in a total dose of 400 mg 
neridronic acid or matching placebo. The complete solution volume of 500 mL should be 
administered at each infusion visit unless treatment is suspended for safety reasons. Any 
administration of less than 500 mL should be noted and recorded in the eCRF. No more than 
4 infusions (400 mg total dose) may be administered to any subject in Treatment Period A.
For subjects with no or mild renal impairment included in Treatment Period B, the full contents of a 
single vial (8 mL) will be diluted in 500 mL normal saline and administered by slow intravenous 
infusion (240 minutes [maximum 260 minutes]) at Visit 11, Visit 12, Visit 13, and Visit 14, 
resulting in a total dose of 400 mg neridronic acid.
A maximum total dose of neridronic acid 800 mg is planned for subjects allocated to neridronic acid 
in Treatment Period A who go on to complete Treatment Period B.
For subjects with moderate renal impairment, the following dose adjustments will be applicable:
CKD-EPI Stage 3a (eGFR 45 mL/min/1.73 m2 to <60 mL/min/1.73 m2)
6 mL of solution from a single vial (corresponding to neridronic acid 75 mg) will be diluted in 
500 mL normal saline and administered by slow intravenous infusion (240 minutes [maximum 
260 minutes]) at each treatment visit, resulting in a total dose of 300 mg neridronic acid or matching 
placebo.
CKD-EPI Stage 3b (eGFR 30 mL/min/1.73 m2 to <45 mL/min/1.73 m2)
5 mL of solution from a single vial (corresponding to neridronic acid 62.5 mg) will be diluted in 
500 mL normal saline and administered by slow intravenous infusion (240 minutes [maximum 
260 minutes]) at each treatment visit, resulting in a total dose of 250 mg neridronic acid or matching 
placebo.
Any decision regarding dose adjustment will be based on the last eGFR value available before 
Visit 2 for Treatment Period A and the last eGFR value available before Visit 11 for Treatment 
Period B.
All infusions must be performed at the trial site under the supervision of medical staff.
Subjects must be assessed for hydration status prior to each infusion to minimize risk for renal 
toxicity. Hydration status will be evaluated by querying subjects about risk factors for volume 
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depletion (poor oral fluid intake, diarrhea) and examining vital signs, mucous membranes, and 
sensorium. Oral fluid intake may be sufficient for correction of mild dehydration.
The IMP discontinuation criteria described in Section 9.3.2 must be evaluated prior to each 
infusion. The 10-day Treatment Period A (or Treatment Period B) may be extended in the event of 
temporary discontinuation of IMP, as described in Section 9.3.2.
The infusion site will be selected to avoid inducing pain in the CRPS-affected limb.
10.3
Method of assigning subjects to treatment (allocation)
On Day 1, subjects who comply with all inclusion criteria and do not meet any of the exclusion 
criteria will be randomly allocated to 1 of the 2 treatment groups in a 1:1 ratio stratified by 
geographic region. Treatment assignment will be performed centrally using an interactive response 
technology system prior to the first intravenous infusion of IMP. The details of the vendor and 
system will be filed in the trial master file.
The investigator (or delegate) must log into the system using their own user identification number 
and a password. The investigator (or delegate) will enter the subject’s number and other information 
required by the system to obtain a medication number. The medication number will then be used to 
select the correct package of IMP to give to the subject.
10.4
Blinding and unblinding
10.4.1
Methods of blinding
The subject’s initial treatment will be blinded until the 26-week analysis. However, investigators 
and subjects will not be informed about the initial treatment allocation at any time before database 
lock of the full trial.
Randomization and blinding will be performed in accordance with the sponsor’s standard operating 
procedures (SOPs).
10.4.2
Methods of unblinding
All persons involved in the conduct, data management, and analysis of the trial will remain blinded 
until unblinding is performed after database lock at the 26-week analysis. Except as indicated below 
for reasons of subject safety, no subject is to be unblinded until the complete dataset has been 
entered into the database and the database has been locked.
Personnel in the sponsor’s departments of clinical trial supply and pharmacokinetics as well as the 
bioanalytical laboratory will be unblinded according to the sponsor’s SOPs.
10.4.3
Identification of IMPs in emergency situations
The investigator and the responsible drug safety department of the sponsor will receive appropriate 
methods for unblinding of single cases, i.e., interactive response technology system access to 
unblinding functionality.
The code may be broken when it is necessary and in that subject’s interest in order to identify the 
IMPs given, e.g., if knowing the identification of the treatment arm would lead to the investigator 
treating the subject differently. In addition, within drug safety, the code may be broken for 
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regulatory reporting, medico-scientific assessment of adverse events, or on request of the qualified 
person for pharmacovigilance.
For every subject whose blind was broken, the following information must be documented on an 
“unblinding an individual subject form”:
•
The reason for, the date, and time of unblinding.
•
The person(s) informed of the treatment allocation must be identified.
In order to maintain the double-blind nature of the trial, the allocation of IMPs for the subject must 
not be communicated further unless required for the surveillance of the subject or if necessary for 
urgent risk to benefit re-evaluation and/or measures for urgent risk minimization.
If required by local regulations, it may be that the IEC, IRB, or the international coordinating 
investigator needs to be informed.
10.5
Allowed and forbidden prior/concomitant medications or therapies
Information on allowed or forbidden prior/concomitant medications or therapies is provided in 
Section 1.4.2.
For the purposes of data reporting by the site, the cutoff for reporting medication as either prior or 
concomitant is defined as the start of the first administration of IMP.
The allowed and forbidden concomitant medications or therapies will be explained to the subject by 
the investigator.
In emergency situations, subjects should be treated according to standard medical practice (see 
Section 11.3.1).
For information about potential drug-drug interactions, see Section 7.3.4.1 of the neridronic acid 
investigator’s brochure.
10.6
Documentation of drug accountability
The principal investigator must ensure that documentation is maintained for the receipt, inventory, 
use, and destruction or return of unused, used, or partially used packages of IMPs. The 
documentation must include IMP name, dates, quantities, subject numbers, batch/serial numbers or 
other identification numbers, expiration dates, and the means to identify the subject to whom it was 
given.
Documentation must be maintained for the checking of drug accountability.
Before the unused IMPs supplied to the trial site are returned or destroyed, the principal investigator 
must allow sponsor representatives to perform drug reconciliation. The entries in the documentation 
will be compared with the returned and residual IMPs and the administration/intake as documented 
in the eCRF, with clarification of any discrepancies or inconsistencies.
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11
COURSE OF THE TRIAL AND CONDITIONS
See Section 1.1.1 for a flow diagram summary of the trial and Section 1.7 for tabular schedules of 
events.
11.1
Course of the trial
Blood samples for bone turnover markers should be collected in the morning under fasted 
conditions at Visits 2, 6, 7, 8, 10, 15, 16, and 17. Therefore, these visits should be attended in a 
fasting state (at least 8 hours).
The site should remind the subject 2 days before the scheduled visits that they should come to the 
site in a fasted state at these visits.
Fasting, non-fasting, or insufficient fasting should be documented at these visits. Non-fasting or 
insufficient fasting will not be documented as a protocol deviation (see Section 3.2).
11.1.1
Enrollment Period
The Enrollment Period consists of an Enrollment Visit (Visit 1) from Day -60 to Day -8 and a 
baseline pain assessment phase from Day -7 to Day -1 during which subjects will record pain 
intensity ratings in the electronic diary. These pain intensity ratings will be used to calculate the 
baseline average pain intensity score.
Additional visits are allowed during the Enrollment Period to confirm normalization of laboratory 
values (e.g., for subjects with vitamin D deficiency, up to a maximum of 4 times repeated 
laboratory testing for vitamin D in 60 days). For details of repeat testing, see Section 1.3.2.
11.1.1.1
Visit 1 (Day -60 to Day -8)
The following evaluations will be performed:
•
Obtain written informed consent (the specific informed consent form for pharmacogenetic
and omics sampling should preferably be signed at Visit 1, but has to be signed at the latest 
at Visit 2 before the sample is taken).
•
Record demographic data (date of signing the informed consent form, sex, race/ethnicity, 
age, height, and body mass index [automatically calculated in the eCRF]).
•
Record medical history.
•
Record CRPS history (for details, see Section 12.2.3.1).
•
Record dental history (for details, see Section 12.2.3.2).
•
Record physical examination outcome.
•
Record body weight.
•
Record vital signs.
•
Record triplicate 12-lead ECG.
•
Record prior/concomitant medications and therapies (dose and dosing frequency data must 
be recorded).
•
Record adverse events.
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•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform a urine ß-HCG pregnancy test.
•
Perform urine drugs of abuse testing.
•
Complete the assessment of the signs and symptoms of CRPS (for details, see 
Section 12.3.6).
•
Dispense subject trial card.
•
Dispense calcium and vitamin D supplements.
•
Review inclusion/exclusion criteria.
•
Dispense electronic diary.
•
Training for electronic diary.
11.1.1.2
Baseline pain assessment phase (Day -7 to Day -1)
In order to calculate the baseline pain intensity score, subjects will be asked to rate their average 
CRPS-related pain intensity using an 11-point NRS once daily (in the evening) during the last 
7 days prior to Visit 2, in the electronic diary. Subjects will also be asked to rate their worst and 
their current CRPS-related pain intensity once daily during the same period of time. The worst and 
average pain will be based on a 24-hour recall period.
11.1.2
Treatment Period A
Infusion visits should be separated by 3-day intervals to the extent possible (i.e., Day 1, Day 4, 
Day 7, and Day 10). Infusion visits on consecutive days are not allowed. The full dosing period 
must not exceed 21 days from the first infusion (Visit 2). To facilitate scheduling, the interval 
between infusion visits may be adapted, provided the 21 day time period is not exceeded and 
discontinuation criteria can be assessed. In case of suspension of treatment due to a suspected safety 
concern or a visit scheduling difficulty, resumption of treatment is allowed upon resolution of 
findings, with sponsor agreement.
11.1.2.1
Visit 2 (Day 1)
The following evaluations will be performed prior to the start of IMP infusion:
•
Record physical examination outcome (change from Visit 1).
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes prior to the start of infusion).
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform semi-quantitative dipstick urinalysis for urinary ACR.
•
Perform a urine ß-HCG pregnancy test.
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•
Perform urine drugs of abuse testing.
•
Complete the assessment of the signs and symptoms of CRPS (for details, see 
Section 12.3.6).
•
Review inclusion/exclusion criteria.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria (for details, see Section 9.3.1).
•
Check IMP suspension criteria (for details, see Section 9.3.2).
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
•
Measure edema, DMA, PPT, and AROM.
•
Ask the subject to complete the PROMIS-29 profile and the PROMIS-EDDEP39 (the 
investigator should review the subject’s answer to the PROMIS EDDEP39 question before 
the subject leaves the site and in case of suicidal ideation the investigator should consider 
involvement of a mental health professional).
•
Ask the subject to complete the 6 neuropathic pain items of the SF-MPQ-2.
•
Ask the subject to complete the PCS.
•
Ask the subject to complete the PSEQ.
•
Ask the subject to complete the PGI-S.
•
Ask the subject to complete the WPAI: CRPS (US sites only).
•
Collect information for medical resources utilization and health economics (US sites only).
•
Take blood for pharmacokinetic evaluation (see Section 1.7.1 for time point).
•
Take blood for bone turnover marker evaluation.
•
Take blood for sIL-2R testing.
•
Take blood for pharmacogenetic and omics testing (see Section 11.1.1.1 for details of 
obtaining informed consent).
Compliance with inclusion and exclusion criteria must be confirmed before allocation to IMP. The 
baseline average pain intensity score must be confirmed prior to allocation by checking the 
electronic diary, which will provide an automatic calculation. A baseline average pain intensity 
score of at least 4 on the 11-point NRS is required.
A subject who has not met average baseline pain intensity requirements due to lack of compliance 
with the electronic diary (at least 4 average pain intensity ratings) may be rescheduled for Visit 2 
(allowed only once), with appropriate re-training to ensure compliance with use of the electronic 
diary. Subjects who do not meet eligibility criteria due to an inadequate average pain level (less 
than 4 on the NRS) will be excluded from the trial.
Once the above evaluations have been performed, the subject will be allocated to IMP using the 
interactive response technology system and the IMP will be administered (for details, see 
Section 10.2).
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During the infusion, a blood sample will be taken for pharmacokinetic evaluation (see Section 1.7.1
for time point).
The following evaluations will be performed after the infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes after the infusion).
•
Record prior/concomitant medications and therapies.
•
Record adverse events.
•
Take blood for pharmacokinetic evaluation (see Section 1.7.1 for time point).
11.1.2.2
Visit 3 (Day 4; ±1 day)
The following evaluations will be performed prior to the start of IMP infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes prior to the start of infusion).
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform semi-quantitative dipstick urinalysis for urinary ACR.
•
Perform a urine ß-HCG pregnancy test.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria (for details, see Section 9.3.1).
•
Check IMP suspension criteria (for details, see Section 9.3.2).
•
Take blood for pharmacokinetic evaluation (see Section 1.7.1 for time point).
Once the above evaluations have been performed, the IMP will be administered (for details, see 
Section 10.2).
The following evaluations will be performed after the infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes after the infusion).
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for pharmacokinetic evaluation (see Section 1.7.1 for time point).
11.1.2.3
Visit 4 (Day 7; ±1 day)
The following evaluations will be performed prior to the start of IMP infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes prior to the start of infusion).
•
Record adverse events.
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•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform semi-quantitative dipstick urinalysis for urinary ACR.
•
Perform a urine ß-HCG pregnancy test.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria (for details, see Section 9.3.1).
•
Check IMP suspension criteria (for details, see Section 9.3.2).
•
Take blood for pharmacokinetic evaluation (see Section 1.7.1 for time point).
Once the above evaluations have been performed, the IMP will be administered (for details, see 
Section 10.2).
The following evaluations will be performed after the infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes after the infusion).
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for pharmacokinetic evaluation (see Section 1.7.1 for time point).
11.1.2.4
Visit 5 (Day 10; ±1 day)
The following evaluations will be performed prior to the start of IMP infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes prior to the start of infusion).
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform semi-quantitative dipstick urinalysis for urinary ACR.
•
Perform a urine ß-HCG pregnancy test.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria (for details, see Section 9.3.1).
•
Check IMP suspension criteria (for details, see Section 9.3.2).
•
Take blood for pharmacokinetic evaluation (see Section 1.7.1 for time point).
Once the above evaluations have been performed, the IMP will be administered (for details, see 
Section 10.2).
During the infusion, a blood sample will be taken for pharmacokinetic evaluation (see Section 1.7.1
for time point).
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The following evaluations will be performed after the infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes after the infusion).
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for pharmacokinetic evaluation (see Section 1.7.1 for time point).
11.1.3
Follow-up Period 1
In case of interruption or suspension of treatment, the first follow-up visit (Visit 6) should be 
scheduled at 4 days (±2 days) after the last infusion visit. All subsequent visits must remain as 
originally scheduled relative to Visit 2 (e.g., Visit 7 occurs at 42 days [6 weeks] ±3 days after 
Visit 2). No more than 4 infusions are allowed in Treatment Period A; any partial infusion 
(exceeding 20 mL) must be counted as 1 infusion.
11.1.3.1
Visit 6 (Day 15 [Week 2]; ±2 days)
The following evaluations will be performed:
•
Record vital signs.
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria.
•
Take blood for pharmacokinetic evaluation (at any time point during the visit).
•
Take blood for bone turnover marker evaluation.
11.1.3.2
Visit 7 (Day 43 [Week 6]; ±3 days)
The following evaluations will be performed:
•
Record vital signs.
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Complete the assessment of the signs and symptoms of CRPS (for details, see 
Section 12.3.6).
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria.
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•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
•
Measure edema, DMA, PPT, and AROM.
•
Ask the subject to complete the PROMIS-29 profile and the PROMIS-EDDEP39 (the 
investigator should review the subject’s answer to the PROMIS EDDEP39 question before 
the subject leaves the site and in case of suicidal ideation the investigator should consider 
involvement of a mental health professional).
•
Ask the subject to complete the 6 neuropathic pain items of the SF-MPQ-2.
•
Ask the subject to complete the PCS.
•
Ask the subject to complete the PSEQ.
•
Ask the subject to complete the PGI-S.
•
Take blood for bone turnover marker evaluation.
•
Ask the subject to complete the PGIC.
11.1.3.3
Visit 8 (Day 85 [Week 12]; +7 days)
Visit 8 must not occur prior to Day 85 in order for the subjects to have complete electronic diary 
data through Week 12 for the calculation of the primary endpoint.
The following evaluations will be performed:
•
Record physical examination outcome (change from Visit 2).
•
Record vital signs.
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Complete the assessment of the signs and symptoms of CRPS (for details, see 
Section 12.3.6).
•
Training on electronic diary as, from Week 12, the electronic diary will ask for weekly 
assessments of pain intensity.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria.
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
•
Measure edema, DMA, PPT, and AROM.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PROMIS-29 profile and the PROMIS-EDDEP39 (the 
investigator should review the subject’s answer to the PROMIS EDDEP39 question before 
the subject leaves the site and in case of suicidal ideation the investigator should consider 
involvement of a mental health professional).
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•
Ask the subject to complete the 6 neuropathic pain items of the SF-MPQ-2.
•
Ask the subject to complete the PCS.
•
Ask the subject to complete the PSEQ.
•
Ask the subject to complete the PGI-S.
•
Ask the subject to complete the WPAI: CRPS (US sites only).
•
Collect information for medical resources utilization and health economics (US sites only).
•
Take blood for bone turnover marker evaluation.
•
Take blood for sIL-2R testing.
•
Take blood for omics testing.
•
Ask the subject to complete the PGIC.
11.1.3.4
Visit 9 (Day 113 [Week 16]; ±4 days)
The following evaluations will be performed:
•
Record vital signs.
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Complete the assessment of the signs and symptoms of CRPS (for details, see 
Section 12.3.6).
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria.
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
•
Ask the subject to complete the pain intensity question (question number 29, GLOBAL07) 
of the PROMIS-29 profile.
•
Ask the subject to complete the PGI-S.
•
Ask the subject to complete the PGIC.
11.1.3.5
Visit 10 (Day 155 [Week 22]; ±4 days)
The following evaluations will be performed:
•
Record vital signs.
•
Record triplicate 12-lead ECG.
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform a urine ß-HCG pregnancy test.
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•
Complete the assessment of the signs and symptoms of CRPS (for details, see 
Section 12.3.6).
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria.
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
•
Ask the subject to complete the pain intensity question (question number 29, GLOBAL07) 
of the PROMIS-29 profile.
•
Ask the subject to complete the PGI-S.
•
Take blood for bone turnover marker evaluation.
•
Ask the subject to complete the PGIC.
11.1.4
Follow-up Period 2
11.1.4.1
Visit 11 (Day 183 [Week 26]; +7 days)
Visit 11 must not occur prior to Day 183, to ensure a full 6 months of follow-up for all subjects.
If Visit 11 is not performed on Day 183, Visit 12 to Visit 15 should proceed in accordance with the 
originally scheduled time windows relative to Visit 11.
The following evaluations will be performed for all subjects:
•
Record physical examination outcome (change from Visit 8).
•
Record body weight.
•
Record vital signs.
•
Record concomitant medications and therapies.
•
Assess further need of concomitant treatment for CRPS (in particular opioids), including 
decreases in dose or frequency as applicable.
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria (for details, see Section 9.3.1).
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
•
Measure edema, DMA, PPT, and AROM.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PROMIS-29 profile and the PROMIS-EDDEP39 (the 
investigator should review the subject’s answer to the PROMIS EDDEP39 question before 
the subject leaves the site and in case of suicidal ideation the investigator should consider 
involvement of a mental health professional).
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•
Ask the subject to complete the 6 neuropathic questions of the SF-MPQ-2.
•
Ask the subject to complete the PCS.
•
Ask the subject to complete the PSEQ.
•
Ask the subject to complete the PGI-S.
•
Ask the subject to complete the WPAI: CRPS (US sites only).
•
Collect information for medical resources utilization and health economics (US sites only).
•
Take blood for sIL-2R testing.
•
Take blood for omics testing.
•
Ask the subject to complete the PGIC.
•
Check the criteria to continue into Treatment Period B.
Decision to go into Treatment Period B
Compliance with the criteria to continue into Treatment Period B must be confirmed before 
allocation to IMP. The pain intensity question (question number 29, GLOBAL07) of the PROMIS-
29 profile has to have a value of at least 4 at Visit 11. Subjects who do not meet the criteria to 
continue into Treatment Period B will continue with the Follow-up Period 2.
11.1.4.1.1
Subjects meeting the criteria to continue into Treatment Period B
For subjects continuing into Treatment Period B, the following evaluations will be performed prior 
to the start of IMP infusion:
•
Record triplicate 12-lead ECG (at least 15 minutes prior to the start of infusion).
•
Perform semi-quantitative dipstick urinalysis for urinary ACR.
•
Perform a urine ß-HCG pregnancy test.
•
Perform urine drugs of abuse testing.
•
Complete the assessment of the signs and symptoms of CRPS (for details, see 
Section 12.3.6).
•
Check IMP suspension criteria (for details, see Section 9.3.2).
•
Take blood for pharmacokinetic evaluation (see Section 1.7.2 for time point).
Once the above evaluations have been performed, the subject will be re-allocated to IMP using the 
interactive response technology system and the IMP will be administered (for details, see 
Section 10.2).
During the infusion, a blood sample will be taken for pharmacokinetic evaluation (see Section 1.7.2
for time point).
The following evaluations will be performed after the infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes after the infusion).
•
Record adverse events.
•
Take blood for pharmacokinetic evaluation (see Section 1.7.2 for time point).
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11.1.4.2
Treatment Period B
Infusion visits should be separated by 3-day intervals to the extent possible (i.e., Day 183, Day 186, 
Day 189, and Day 192). Infusion visits on consecutive days are not allowed. The full dosing period 
must not exceed 21 days from the first infusion of Treatment Period B (Visit 11). To facilitate 
scheduling, the interval between infusion visits may be adapted, provided the 21 day time period is 
not exceeded and discontinuation criteria can be assessed. In case of suspension of treatment due to 
a suspected safety concern or a visit scheduling difficulty, resumption of treatment is allowed upon 
resolution of findings, with sponsor agreement. In case of interruption or suspension of treatment, 
the first follow-up visit (Visit 15) should be scheduled at 4 days (±2 days) after the last infusion 
visit of Treatment Period B. All subsequent visits must remain as originally scheduled relative to 
Visit 11. No more than 4 infusions are allowed in Treatment Period B; any partial infusion 
(exceeding 20 mL) must be counted as 1 infusion.
11.1.4.2.1
Visit 12 (Day 186; ±1 day) - only subjects receiving a second treatment course
The following evaluations will be performed prior to the start of IMP infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes prior to the start of infusion).
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform semi-quantitative dipstick urinalysis for urinary ACR.
•
Perform a urine ß-HCG pregnancy test.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria (for details, see Section 9.3.1).
•
Check IMP suspension criteria (for details, see Section 9.3.2).
•
Take blood for pharmacokinetic evaluation (see Section 1.7.2 for time point).
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
Once the above evaluations have been performed, the IMP will be administered (for details, see 
Section 10.2).
The following evaluations will be performed after the infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes after the infusion).
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for pharmacokinetic evaluation (see Section 1.7.2 for time point).
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11.1.4.2.2
Visit 13 (Day 189; ±1 day) - only subjects receiving a second treatment course
The following evaluations will be performed prior to the start of IMP infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes prior to the start of infusion).
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform semi-quantitative dipstick urinalysis for urinary ACR.
•
Perform a urine ß-HCG pregnancy test.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria (for details, see Section 9.3.1).
•
Check IMP suspension criteria (for details, see Section 9.3.2).
•
Take blood for pharmacokinetic evaluation (see Section 1.7.2 for time point).
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
Once the above evaluations have been performed, the IMP will be administered (for details, see 
Section 10.2).
The following evaluations will be performed after the infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes after the infusion).
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for pharmacokinetic evaluation (see Section 1.7.2 for time point).
11.1.4.2.3
Visit 14 (Day 192; ±1 day) - only subjects receiving a second treatment course
The following evaluations will be performed prior to the start of IMP infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes prior to the start of infusion).
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform semi-quantitative dipstick urinalysis for urinary ACR.
•
Perform a urine ß-HCG pregnancy test.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria (for details, see Section 9.3.1).
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Check IMP suspension criteria (for details, see Section 9.3.2).
•
Take blood for pharmacokinetic evaluation (see Section 1.7.2 for time point).
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
Once the above evaluations have been performed, the IMP will be administered (for details, see 
Section 10.2).
During the infusion, a blood sample will be taken for pharmacokinetic evaluation (see Section 1.7.2
for time point).
The following evaluations will be performed after the infusion:
•
Record vital signs.
•
Record triplicate 12-lead ECG (at least 15 minutes after the infusion).
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for pharmacokinetic evaluation (see Section 1.7.2 for time point).
11.1.4.3
Visit 15 (Day 197 [Week 28]; +7/-2 days) - only subjects receiving a second 
treatment course
The following evaluations will be performed:
•
Record vital signs.
•
Record triplicate 12-lead ECG.
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria.
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
•
Ask the subject to complete the PROMIS-29 profile.
•
Ask the subject to complete the 6 neuropathic questions of the SF-MPQ-2.
•
Ask the subject to complete the PGI-S.
•
Take blood for pharmacokinetic evaluation (at any time point during the visit).
•
Take blood for bone turnover marker evaluation.
•
Ask the subject to complete the PGIC.
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11.1.4.4
Visit 16 (Day 253 [Week 36]; ±7 days) - for all subjects
The following evaluations will be performed:
•
Record vital signs.
•
Record concomitant medications and therapies.
•
Assess further need of concomitant treatment for CRPS (in particular opioids), including 
decreases in dose or frequency as applicable.
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Complete the assessment of the signs and symptoms of CRPS.
•
Compliance assessment for electronic diary.
•
Check trial discontinuation criteria.
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
•
Measure edema, DMA, PPT, and AROM.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PROMIS-29 profile and the PROMIS-EDDEP39 (the 
investigator should review the subject’s answer to the PROMIS EDDEP39 question before 
the subject leaves the site and in case of suicidal ideation the investigator should consider 
involvement of a mental health professional).
•
Ask the subject to complete the 6 neuropathic questions of the SF-MPQ-2.
•
Ask the subject to complete the PCS.
•
Ask the subject to complete the PSEQ.
•
Ask the subject to complete the PGI-S.
•
Ask the subject to complete the WPAI: CRPS (US sites only).
•
Collect information for medical resources utilization and health economics (US sites only).
•
Take blood for bone turnover marker evaluation.
•
Ask the subject to complete the PGIC.
11.1.4.5
Visit 17 (Day 365 [Week 52]; +7 days) - for all subjects
Visit 17 must not occur prior to Day 365, to ensure that the subjects are followed up for a full 
12 months.
The following evaluations will be performed:
•
Record physical examination outcome (change from Visit 11).
•
Record body weight.
•
Record vital signs.
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•
Record triplicate 12-lead ECG.
•
Record concomitant medications and therapies.
•
Record adverse events.
•
Take blood for safety laboratory testing.
•
Collect urine for quantitative urinalysis at the central laboratory.
•
Perform dipstick urinalysis.
•
Perform a urine ß-HCG pregnancy test.
•
Complete the assessment of the signs and symptoms of CRPS.
•
Compliance assessment for electronic diary.
•
Collect electronic diary.
•
Ask the subject to record the average, worst, and current pain on the tablet computer at the 
site.
•
Measure edema, DMA, PPT, and AROM.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PROMIS-29 profile and the PROMIS-EDDEP39 (the 
investigator should review the subject’s answer to the PROMIS EDDEP39 question before 
the subject leaves the site and in case of suicidal ideation the investigator should consider 
involvement of a mental health professional).
•
Ask the subject to complete the 6 neuropathic questions of the SF-MPQ-2.
•
Ask the subject to complete the PCS.
•
Ask the subject to complete the PSEQ.
•
Ask the subject to complete the PGI-S.
•
Ask the subject to complete the WPAI: CRPS (US sites only).
•
Collect information for medical resources utilization and health economics (US sites only).
•
Take blood for bone turnover marker evaluation.
•
Ask the subject to complete the PGIC.
11.2
Examination hierarchy and time windows
Pain evaluations and ECGs should be taken before invasive procedures. When practical, blood 
samples for safety laboratory and pharmacokinetic evaluation should be taken after all non-invasive 
procedures (including completion of questionnaires) have been finished.
11.3
Conditions during the trial
11.3.1
Medical care
Hospitalization of subjects for the entire treatment or certain trial periods, for logistical reasons, is 
allowed, if agreed by the sponsor prior to hospitalization for this reason.
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For any adverse events, a causal or symptomatic treatment according to standard medical practice 
should be provided if deemed necessary by the investigator. The medical care given to, and medical 
decisions made on behalf of the subjects must be the responsibility of a qualified physician.
See the guidance in the investigator’s brochure for precautions and the handling of emergencies.
11.3.2
Meals and fluid intake restrictions
Visits 2, 6, 7, 8, 10, 15, 16, and 17 should be attended in a fasting state (at least 8 hours).
Light meals are allowed after sampling for bone turnover markers and may be provided before, 
during, and/or after IMP infusions during Treatment Period A (Visit 2 to Visit 5) and Treatment 
Period B (Visit 11 to Visit 14).
Fluid intake is recommended prior to and during the infusions. Subjects must be well hydrated prior 
to the start of infusions.
11.3.3
Dental hygiene
Subjects should adhere to the following recommendations for good dental hygiene throughout the 
trial:
•
Brush teeth twice a day (with a fluoride toothpaste).
•
Floss regularly to remove plaque from between teeth.
•
Continue with routine dental visits (as recommended by their dentist) for a check-up and 
professional cleaning.
Subjects will be advised to notify the investigator if they experience any dental pain or swelling of 
the gums, infection in the mouth, any pain related to use of dentures, or are planning dental work.
11.3.4
Counseling of women of reproductive age
All women, including those with tubal ligation, will be considered to be of child-bearing potential 
unless they have been postmenopausal for at least 2 years or have undergone a hysterectomy.
Trial subjects must use contraception as defined in inclusion criterion 6.
Women will be counseled to contact the investigator or site staff immediately if pregnancy is 
suspected.
11.4
Subject trial cards
Subjects who are enrolled in the trial will receive a subject trial card (the time of card distribution is 
given in Section 1.7.1 and Section 1.7.2). The trial card will list the following information:
•
Name of the subject and a statement that he/she is currently participating in a clinical trial.
•
Trial code.
•
Dates of all individual visits.
•
Name of the principal investigator for that trial site.
•
Contact (telephone) number at the trial site.
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11.5
Provisions of any additional care of subjects after trial termination
Subjects who complete or discontinue from the trial should continue treatment with their regular 
physicians in accordance with standard practices.
12
TRIAL ASSESSMENTS
12.1
Overview of blood sampling in this trial
The total blood volume drawn per subject during the trial is estimated to be approximately 314 mL 
for subjects included in Treatment Period B and approximately 230 mL for subjects not included in 
Treatment Period B (unless additional blood is required for repeated assessment due to an abnormal 
laboratory value, adverse event, or technical reason such as hemolysis of the blood sample).
Sampling times are given in the schedules of events (Section 1.7).
Table 3:
Planned approximate blood sampling volumes collected from each subject
Test
Unit volume of 
blood
Number of 
samples
Total
Pharmacokinetic evaluation
4 mL
11
44 mL
Additional pharmacokinetic evaluation for subjects in 
Treatment Period B
4 mL
11
44 mL
Sampling for bone turnover markers
7.5 mL
7
52.5 mL
Additional sampling for bone turnover markers for 
subjects in Treatment Period B
7.5 mL
1
7.5 mL
Sampling for pharmacogenetic testing (optional)
5 mL
1
5 mL
Sampling for omics testing (optional)
5 mL
3
15 mL
Sampling for sIL-2R testing
5 mL
3
15 mL
Sampling for central safety laboratory testing:
Hematology
3 mL
12
36 mL
Clinical chemistry
5 mL
12
60 mL
Parathyroid hormone
3 mL
1
3 mL
Additional sampling for central safety laboratory testing 
for subjects in Treatment Period B:
Hematology
3 mL
4
12 mL
Clinical chemistry
5 mL
4
20 mL
Total for subjects included in Treatment Period B
70
314.0 mL
Total for subjects not included in Treatment Period B
50
230.5 mL
The volume of blood taken may be individually variable due to local practices and the potential need for resampling.
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12.2
Collection of demographic data and other baseline characteristics
12.2.1
Demographic data
Demographic data to be collected and recorded for this trial include date of signing the informed 
consent form, sex, race/ethnicity, age, height, and body mass index.
Body mass index will be automatically calculated in the eCRF.
12.2.2
Prior and concomitant medication or therapies
All medication requiring prescriptions (including oral contraceptives), over-the-counter medication
(including herbals and vitamins), and therapies (including medical devices and therapies such as 
e.g., massage or cognitive behavioral therapy) used within 3 months prior to enrollment and up to 
the end of the trial must be recorded in the eCRF. All failed CRPS medication must be added in the 
eCRF (including medications stopped before 3 months prior to enrollment). Any change in dosage, 
regimen, frequency, or route, must be recorded in the eCRF as a new entry.
For the concomitant medication, the trade name, dose, dose unit, frequency, route, reason for use, 
start date, and stop date have to be recorded in the eCRF.
12.2.3
Relevant prior/concomitant disease or surgical interventions
All medical history relevant to CRPS (including family history of CRPS) should be documented in 
the eCRF (for details, see Section 12.2.3.1). Additional medical history for the previous 3 years as 
well as medical history from prior to 3 years that may be considered relevant should also be 
documented in the eCRF.
There is no requirement to obtain copies of medical records from treating physicians to document 
medical history.
12.2.3.1
Diagnosis of CRPS
Diagnosis of CRPS according to the clinical diagnostic criteria in Table 4 must be documented at 
the Enrollment Visit upon examination of the subject. It is the absolute responsibility of the 
investigator to make the diagnosis of CRPS according to the correct diagnostic criteria. Application 
of the CRPS diagnostic criteria requires identification of an affected limb. Distal to mid-limb 
involvement (typically hand or foot), with or without proximal spread, must be present. Evidence of 
asymmetrical signs and symptoms, relative to the contralateral (less affected) limb, is a requirement 
for fulfilling the diagnostic criteria. A precise location of the CRPS, consistent with the location of
signs and symptoms, must be documented in the eCRF. If more than 1 limb is considered to be 
affected, the trial-designated CRPS most affected-limb must be readily distinguished based on 
asymmetrical signs and symptoms, relative to the contralateral limb, and the subject must be able to 
differentiate pain in the affected limb from pain in any other affected limbs. Ongoing, 
disproportionate pain and a lack of other diagnosis that better explains the signs and symptoms must 
also be confirmed at the Enrollment Visit.
Diagnosis of CRPS involving an atypical body part (e.g., trunk, breasts, pelvic region, lower 
back, face, shoulder, or hip) is not permitted for this trial.
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Table 4:
Complex regional pain syndrome clinical diagnostic criteria recommended by the 
IASP; “Budapest clinical criteria”
1.
Continuing pain, which is disproportionate to any inciting event.
2.
Must report at least one symptom in three of the four following categories:
−
Sensory: reports of hyperesthesia and/or allodynia.
−
Vasomotor: reports of temperature asymmetry and/or skin color changes and/or skin 
color asymmetry.
−
Sudomotor/edema: reports of edema and/or sweating changes and/or sweating 
asymmetry.
−
Motor/trophic: reports of decreased range of motion and/or motor dysfunction 
(weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin).
3.
Must display at least one sign at time of evaluation in two or more of the following 
categories:
−
Sensory: evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch 
and/or deep somatic pressure and/or joint movement).
−
Vasomotor: evidence of temperature asymmetry and/or skin color changes and/or 
asymmetry.
−
Sudomotor/edema: evidence of edema and/or sweating changes and/or sweating 
asymmetry.
−
Motor/trophic: evidence of decreased range of motion and/or motor dysfunction 
(weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin).
4.
There is no other diagnosis that better explains the signs and symptoms.
IASP = International Association for the Study of Pain.
Source: Harden et al. 2010a
In accordance with procedures for validation of these criteria, symptoms will be assessed with a 
recall period “since the onset of CRPS”. Signs must be present, i.e., observed by the examiner, 
during the evaluation at the Enrollment Visit. Subjects will be examined for 8 signs (observed on 
examination, yes or no): hyperalgesia to pinprick; allodynia (light touch, deep joint pressure, 
vibration, cold, and heat); temperature asymmetry by palpation (affected side cooler or warmer than 
the contralateral side); skin color asymmetry (red, blue or pale, mottled, or scar); asymmetric 
edema; sweating asymmetry (increased or decreased on the affected side); dystrophic changes 
(nails, hair, or skin); and motor changes (tremor, dystonia, decreased AROM, or weakness).
Medical history related to CRPS must include the following: date and description of precipitating 
event (e.g., type of trauma, surgery [including any information on whether there was a major nerve 
injury]; if no precipitating event is known, document as unknown), the specific location of CRPS, 
including the affected limb (if more than 1 limb is affected, the most painful limb as well as any 
other affected limb must be identified), the date of onset of symptoms, the date of CRPS diagnosis, 
and the type of CRPS (CRPS-I or CRPS-II). Any documentation supporting the diagnosis of CRPS, 
including any assessments used to rule out alternative diagnoses, will be retained.
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12.2.3.2
Dental history
Dental history will include the date of last dental visit; dental extractions and other invasive dental 
surgery in the past 3 months prior to the Enrollment Visit; current evidence of dental or periodontal 
disease, gum injury due to dentures, or other dental history that may pre-dispose to risk of 
medication-related osteonecrosis of the jaw.
12.2.4
Other baseline characteristics
12.2.4.1
Physical examination
Physical examination should include assessments of the general condition, skin, eyes, ears, nose and 
throat, mouth (including teeth and gums), head, neck, and thyroid, heart, lung, chest, abdomen, 
kidneys, liver, lymphatic, musculoskeletal, and neurological systems.
Prior to allocation to treatment, any clinically relevant findings from the physical examination will 
be documented as part of the medical history.
12.2.4.2
Urine drugs of abuse test
Urine samples will be provided by the subject at Visit 1 and Visit 2 (and Visit 11 for subjects going 
into Treatment Period B) for local testing for drugs of abuse using a urinary dipstick (performed at 
the site). Only test results for the following drugs of abuse will be recorded in the eCRF:
•
Cocaine, MDMA (3,4-methylendioxy methamphetamine, ecstasy), amphetamines, 
cannabinoids.
Subjects who are receiving stable doses of prescribed medications containing amphetamines, 
benzodiazepines, cannabinoids, or opioids will not be excluded from the trial even if the test is 
positive.
12.3
Collection of efficacy data
The following efficacy data will be collected: pain intensity, CRPS Severity Score, measurements 
of edema, DMA, PPT, AROM, PGIC, PGI-S, EQ-5D-5L, PROMIS-29 profile and the PROMIS-
EDDEP39, the 6 neuropathic pain items of the SF-MPQ-2, PCS, and PSEQ.
For the timings of assessments, see the schedules of events (Section 1.7).
12.3.1
Pain intensity
Pain intensities will be recorded in electronic diaries at home and on tablet computers maintained at 
the sites.
12.3.1.1
Electronic diary
Subjects will be asked to record their average, worst, and current CRPS-related pain intensity once
daily in the electronic diary (in the evening), using an 11-point NRS (from 0 = “no pain” to 
10 = “pain as bad as you can imagine”) starting at Visit 1 and continuing until Visit 8. Worst and 
average pain intensity will be for a 24-hour recall period.
After Visit 8 up to Visit 17, subjects will be asked to record their average, worst, and current CRPS-
related pain intensity once weekly in the electronic diary (in the evening) using the same 11-point 
NRS and a 24-hour recall period.
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0
1
2
3
4
5
6
7
8
9
10
No 
pain
Pain as bad as you can 
imagine
Average pain assessment
Subjects will be asked to record their average CRPS-related pain intensity for the previous 24 hours.
The subjects will be asked to answer the following question:
“Please rate your pain by selecting the one number that best describes your pain on average during 
the last 24 hours.”
Worst pain assessment
Subjects will be asked to record their worst CRPS-related pain intensity for the previous 24 hours.
The subjects will be asked to answer the following question:
“Please rate your pain by selecting the one number that best describes your pain at its worst during 
the last 24 hours.”
Current pain assessment
Subjects will be asked to record their current CRPS-related pain intensity.
The subjects will be asked to answer the following question:
“Please rate your pain by selecting the one number that best describes how much pain you have 
right now.”
12.3.1.2
Site tablet computer
At the visits indicated in the schedules of events (Section 1.7), the subjects will be asked to record 
the pain intensity ratings for average, worst, and current CRPS-related pain directly on a tablet 
computer maintained at the site. Worst and average pain intensity ratings in this case will be based 
on a 24-hour recall period.
Average pain assessment
Subjects will be asked to record their average CRPS-related pain intensity for the previous 24 hours.
The subjects will be asked to answer the following question:
“Please rate your pain by selecting the one number that best describes your pain on average during 
the last 24 hours.”
Worst pain assessment
Subjects will be asked to record their worst CRPS-related pain intensity for the previous 24 hours.
The subjects will be asked to answer the following question:
“Please rate your pain by selecting the one number that best describes your pain at its worst during 
the last 24 hours.”
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Current pain assessment
Subjects will be asked to record their current CRPS-related pain intensity.
The subjects will be asked to answer the following question:
“Please rate your pain by selecting the one number that best describes how much pain you have 
right now.”
12.3.1.3
Pain intensity question of the PROMIS-29 profile
At Visit 11, the pain intensity question (question number 29, GLOBAL07) of the PROMIS-29 
profile (Section 18.3.4) will be used as 1 of the criteria for continuing into Treatment Period B. At 
Visit 9 and Visit 10 the PROMIS pain question will be used to monitor efficacy.
The subjects will be asked to answer the following question on an 11-point NRS (0 = no pain, 
10 = worst imaginable pain):
“In the past 7 days, how would you rate your pain on average?”
12.3.2
Dynamic mechanical allodynia
Allodynia is defined as pain in response to a non-nociceptive stimulus. In cases of mechanical 
allodynia, even gentle mechanical stimuli such as a slight bending of hairs can evoke pain. The 
DMA is assessed by the investigator, documented in the source data, and transferred to the eCRF. A 
Q-tip fixed to an elastic strip exerting a force of 100 mN (Ziegler et al. 1999) is applied in a single 
sweeping motion (1 cm to 2 cm length) on the skin of the affected limb.
The subjects are asked to judge the stimulus intensity on an NRS (0 to 10), with “0” in this case 
meaning “no pain”, while each “pricking”, “stinging” or “burning” sensation is defined as a painful 
sensation, being evaluated by giving a value greater than “0”. A value of “10” corresponds to the 
individual maximum pain imaginable. The tactile stimulus is tested 5 times. If the subject reports a 
value of “10”, then no further test will be performed for the respective visit. The degree of pain 
sensitivity is calculated by the geometrical mean of the pain ratings given (Maier et al. 2010).
12.3.3
Pressure pain threshold
The PPT is assessing the level of pressure causing deep joint or muscle pain. In CRPS subjects, 
light, normally non-painful pressure applied at joints or muscles causes pain in the deep somatic 
tissues (Baron et al. 2010). The PPT is assessed by the investigator on both affected and unaffected 
limbs by using a pressure algometer (contact area 1 cm2), documented in the source data, and 
transferred to the eCRF. The threshold for pressure induced pain is measured on the thenar 
muscle/abductor hallucis muscle, starting with the unaffected limb. Measurements are repeated in 
3 series of slowly increasing stimulus intensities (at a rate of about 50 kPa/s). The subject must not 
be able to look at the readings during the measurement. Data are averaged for the each of the 
3 series of measurements. For the final PPT, the arithmetic mean of all 3 consecutive measurements 
is calculated (Rolke et al. 2010 and Mainka et al. 2014).
The ratio of the thresholds of the affected and the unaffected limb will be calculated.
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12.3.4
Edema measurement
Edema will be measured by the investigator with measurement tape using the figure-of-eight 
method at both the affected and contralateral unaffected limb for all subjects having edema as a 
positive CRPS sign at baseline (based on clinical judgment; sign “Asymmetric edema” ticked “yes” 
on the CRPS Severity Score at Visit 2) and will be documented in the source data and transferred to 
the eCRF. At each visit, first the unaffected limb has to be measured to accustom the subject to the 
measurements, followed by the affected limb. Each measurement of the limbs will be performed 
3 times. The average of the 3 measurements will be used for further analysis.
The ratio of the averages of the affected and the unaffected limb will be calculated.
Detailed instructions and training describing in depth the figure-of-eight method for measuring 
edema in both hands or feet will be provided to the investigators.
12.3.5
Active range of motion measurement
The AROM is the range of movement through which a subject can actively (without assistance) 
move a joint using the adjacent muscles. Measuring the AROM does not involve any external 
stimulation; the subject is not touched and decides how far to move. The magnitude of the AROM 
can be influenced by other factors not directly related to the joint, such as the subject’s motivation. 
In order to maximize the reliability of measurements, a rigid measurement protocol and valid and 
reliable measurement instruments were developed. Detailed instructions and in depth training will 
be provided to the investigators.
The subject has to be instructed not to exceed the pain limit in order to avoid increase of 
complaints, which could influence future measurements and treatment outcome. 
For subjects having decreased AROM at baseline (diagnosed based on clinical judgment; sign 
“Motor abnormalities” ticked “yes”, sub-category “decreased AROM” ticked “yes” on the CRPS 
Severity Score at baseline [Visit 2]), both affected and unaffected limbs will be measured using a 
goniometer, first the unaffected extremity to accustom the patient to the measurements, followed by 
the affected extremity. The AROM is measured only during active flexion and extension (i.e., 
sagittal plane, transversal axis) of the wrist or ankle, respectively.
The AROM in each of the unaffected and affected limbs will be measured 2 times. The results of 
both measurements will be documented; only the best performance of the 2 repetitions will be used 
for further analysis.
The ratio of the AROM of the affected and the unaffected limb will be calculated.
12.3.6
CRPS Severity Score
Signs and symptoms of CRPS (Section 18.4) will be assessed by the investigator and recorded 
using the tablet computers maintained at the sites. Subjects will be queried on 8 self-reported 
symptoms (queried yes or no): continuous, disproportionate pain; allodynia and/or hyperalgesia; 
temperature asymmetry; color asymmetry; sweating asymmetry; edema; dystrophic changes; and 
motor abnormalities. Symptoms will be assessed based on a recall period of 48 hours. Subjects will 
be examined for 8 signs (observed on examination, yes or no): hyperalgesia to pinprick; allodynia; 
temperature asymmetry by palpation; skin color asymmetry; sweating asymmetry; asymmetric 
edema; dystrophic changes; and motor changes (please refer to Section 12.2.3.1 and Section 18.4
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for the description of the signs and symptoms). Each sign or symptom is assigned a dichotomous 
value (1 = presence; 0 = absence). The resulting score ranges from 0 to 16, with higher scores 
indicating greater CRPS severity (Harden et al. 2010b).
12.3.7
Patient Global Impression of Change
The PGIC will be assessed using the tablet computers maintained at the sites. The 7-point PGIC is a 
complementary assessment of analgesic efficacy. Subjects respond to the question “Since the start 
of the trial, my overall status is:” with 1 of 7 possible responses (very much improved, much 
improved, minimally improved, no change, minimally worse, much worse, very much worse; 
Section 18.3.1). A response of very much improved or much improved is generally regarded as a 
clinically important outcome. As “change” is conceptually inherent in the questionnaire, no baseline 
assessment can be performed.
12.3.8
Patient Global Impression of Severity
The PGI-S will be assessed by the subjects using the tablet computers maintained at the sites. The 
5-point PGI-S is a 1-item questionnaire designed to assess a patient’s impression of disease 
severity.
Subjects are asked to best describe their CRPS symptoms over the past week with 1 of 5 possible 
responses (none, mild, moderate, severe, very severe; Section 18.3.2).
12.3.9
EuroQoL-5 dimension-5 level
The EQ-5D-5L health questionnaire (Section 18.3.3) will be completed by all subjects using the 
tablet computers maintained at the sites. The EQ-5D-5L has 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each of the 5 dimensions has 5 possible levels: 
no problems, slight problems, moderate problems, severe problems, and extreme problems. An 
index (total) score will be calculated from data from all 5 dimensions using an index value 
calculator that can be downloaded from the EuroQol website. For the US general population, the 
possible EQ-5D-5L index scores range from -0.109 (i.e., 55555) to 1.0 (i.e., 11111) on a scale 
where 0.0 = death and 1.0 = perfect health. The EQ-VAS ranges from 0 (worst imaginable health) 
to 100 (best imaginable health). A higher score represents better overall health.
12.3.10
PROMIS-29 profile and the PROMIS-EDDEP39
The PROMIS-29 profile (Section 18.3.4) assesses 7 domains, i.e., depression, anxiety, physical 
function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and 
activities, each with 4 questions and a recall period of 7 days (Cella et al. 2007).
The PROMIS-29 Profile version 2.0 will be completed by the subjects using the tablet computers 
maintained at the sites.
In addition, suicidal ideation will be assessed using the PROMIS-EDDEP39 (Section 18.3.5), which 
is Question EDDEP39 of the PROMIS Item Bank version 1.0 – Emotional Distress – Depression 
(Pilkonis et al. 2011).
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12.3.11
Short-Form McGill Pain Questionnaire 2: 6 neuropathic pain items
The SF-MPQ-2 is a single measure of the major symptoms of both neuropathic and non-
neuropathic pain. The pain qualities will be assessed using the 6 neuropathic items from the 
SF-MPQ-2 (Section 18.3.6).
Subjects will be asked to consider and report only the pain related to the CRPS when completing 
the instrument using the tablet computers maintained at the sites.
12.3.12
Pain Catastrophizing Scale
The PCS (Section 18.3.7) will be used as a measurement tool to capture pain catastrophizing; the 
scale will be completed by the subjects using the tablet computers maintained at the sites.
12.3.13
Pain Self Efficacy Questionnaire
The PSEQ (Section 18.3.8) will be used to capture pain self-efficacy and is completed by the 
subjects using the tablet computers maintained at the sites.
12.4
Collection of safety data
The following safety data will be collected: adverse events, vital signs, 12-lead ECGs, safety 
laboratory parameters, physical examination findings, and urine ß-HCG pregnancy test outcome.
For the timings of assessments, see the schedules of events (Section 1.7).
Clinically relevant abnormal values (investigator’s judgment) must be recorded as adverse events.
12.4.1
Adverse events
Adverse events will be documented from the time of enrollment (i.e., the time the informed consent 
form is signed) up to the time of the last protocol scheduled contact, i.e., date of last visit/contact 
(can be a phone call, e.g., in case of withdrawal). 
Definition of adverse events
An adverse event is any untoward medical occurrence in a subject enrolled in a clinical trial. An 
adverse event can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.
Pre-existing diseases or conditions occurring before enrollment are not considered to be adverse 
events unless there is an untoward change in intensity, frequency, or quality after enrollment. 
Lack of efficacy, as such, is not considered to be an adverse event while its consequences (e.g., 
deterioration of the treated disease) are considered to be an adverse event.
A newly diagnosed pregnancy of an enrolled female subject will not be considered an adverse event
itself unless it is suspected that the trial treatment interacted with a contraceptive method. In this 
case, the pregnancy will be considered an adverse event. A congenital anomaly as an outcome of a 
pregnancy will be considered a serious adverse event (SAE).
All newly diagnosed pregnancies of enrolled female subjects must be reported to the sponsor’s 
Drug Safety Department within 24 hours after first knowledge. These pregnancies will be 
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documented using a pregnancy reporting form with all available information provided and followed 
up to determine the outcome post parturition.
For newly diagnosed pregnancies of partners of enrolled subjects, a reasonable attempt (i.e., due 
diligence) must be made to report the pregnancy to the sponsor’s Drug Safety Department within 
24 hours after first knowledge.
Definition of serious adverse events
An SAE is any untoward medical occurrence that at any dose:
•
Results in death.
•
Is life-threatening.
•
Requires inpatient hospitalization or prolongation of existing hospitalization.
•
Results in persistent or significant disability/incapacity.
•
Is a congenital anomaly/birth defect.
•
Is considered a clinically important medical event. The medical concepts included in 
Section 18.1 should be taken into account when applying this seriousness criterion.
An elective hospital admission, e.g., for pre-planned surgery, will not be considered an SAE if 
documented at enrollment. Short-lasting (<24 hours) hospital admissions, e.g., for clinical check-
ups, not meeting any of the other above mentioned criteria will also not be considered SAEs.
Special procedures for serious adverse events
If SAEs occur that are not tolerable, the investigator will decide whether to stop the trial 
participation and/or treatment of the subject. For further details, see Section 9.3.
Expectedness of adverse events
Expectedness will be assessed by the sponsor.
An unexpected adverse event is one where the nature or intensity is not consistent with the 
information in the neridronic acid investigator’s brochure.
Furthermore, reports that add significant information about the specificity or severity of a known, 
already documented adverse reaction constitute unexpected adverse events. For example, an
adverse event more specific or more severe than expected would be considered “unexpected”.
Definition of adverse drug reactions
An adverse drug reaction is any untoward and unintended response to an IMP or a medicinal 
product related to any dose administered.
A list of adverse drug reactions seen for the IMP is given in the reference safety information 
(neridronic acid investigator’s brochure).
Documentation of adverse events 
The subjects will be questioned about possible adverse events with non-leading questions before 
administration of the IMP and at regular intervals thereafter as defined in Section 1.7.
All adverse events reported spontaneously by subjects at any time point will also be documented.
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All adverse events will be documented in the eCRF with the following information where 
appropriate:
•
Description (adverse event reported term).
•
Start date/time.
•
End date/time or continuation.
•
Whether adverse event was serious.
•
Intensity.
•
Outcome.
•
Action taken with IMP.
•
Countermeasures.
•
Causal relationship to IMP.
Definition of intensity 
The clinical intensity of an adverse event will be classified as:
Mild:
Signs and symptoms that can be easily tolerated. Symptoms can be ignored and disappear when the 
subject is distracted.
Moderate:
Symptoms cause discomfort but are tolerable; they cannot be ignored and affect concentration.
Severe:
Symptoms which affect usual daily activity.
For adverse events where the intensity changes over time, the maximum intensity observed during 
the whole duration of the adverse event will be documented. 
Adverse events occurring in the Enrollment Period but before first administration of an IMP and 
worsening on or after IMP administration will be documented as new adverse events.
Definition of outcome at the time of last observation
The outcome at the time of last observation will be classified as:
•
Recovered/Resolved.
•
Recovering/Resolving.
•
Not recovered/Not resolved.
•
Recovered/Resolved with sequelae.
•
Fatal.
•
Unknown (unknown should only be used, if at the time of the last visit for a subject in a 
trial, the outcome of the adverse event is unknown to the investigator, e.g., because the 
subject is lost to follow-up).
Definition of countermeasures 
“Countermeasures” will be defined as:
None:
No countermeasure given.
Newly started 
medication:
A newly started medication or change in dose or route of application of a medication due 
to the adverse event (to be listed on the prior/concomitant medication page) that is used 
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as a countermeasure.
Trial discontinuation:
It was necessary to discontinue the subject from the trial due to the adverse event.
Other:
All other countermeasures, e.g., physical therapy, surgery.
Except for none, multiple countermeasures for 1 adverse event can be recorded.
Classification of action taken with IMP when an adverse event occurs:
•
Dose not changed.
•
Drug interrupted.
•
Drug withdrawn.
•
Not applicable.
•
Unknown.
Classification of causation
The causal relationship of an adverse event to IMP will be classified using the following 
terminology. The given criteria for each term are for consideration and are neither exhaustive nor 
required to be fulfilled in total for the selection of the respective term:
Terms for classification 
of causation
Criteria for the selection of causality classification terms
Conditional/ 
Unclassified:
Additional data for a proper assessment are under examination.
Unassessable/ 
Unclassifiable:
The available data cannot be judged because information is insufficient or contradictory, 
and cannot be supplemented or verified. 
Not related:
Data with sufficient evidence to accept that there is no causal relationship to IMP 
administration (i.e., there is no temporal relationship to IMP administration or proved 
other cause). 
Unlikely:
Data without sufficient evidence to accept that there is no causal relationship to IMP 
administration, but also with no evidence or argument to suggest a causal relationship 
(e.g., the temporal relationship to IMP administration makes a causal relationship 
improbable, and other drugs, chemicals, or underlying disease[s] provide plausible 
explanations). 
Possible:
Data with limited evidence or argument to suggest a causal relationship (e.g., there is a 
reasonable time sequence to administration of the drug, but the adverse event could also 
be explained by concurrent disease[s] or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear). 
Probable/likely:
Data with sufficient evidence or argument to suggest a causal relationship (e.g., there is a 
reasonable time sequence to administration of the drug, the adverse event is unlikely to 
be attributed to concurrent disease[s] or other drugs or chemicals, and a clinically 
reasonable response on withdrawal [dechallenge]).
Certain:
Data with clear evidence for a causal relationship (i.e., a clinical event, including 
laboratory test abnormality, occurs in a plausible time relationship to drug administration, 
and it cannot be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug [dechallenge] should be well defined and clinically 
plausible, using a satisfactory rechallenge procedure if appropriate).
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Follow-up of subjects with an adverse event
Any adverse event or clinically relevant abnormal laboratory or vital sign result will be followed 
until it reaches a satisfactory resolution, or becomes stable, or clinical judgment indicates that 
further evaluation is not warranted. 
Notification of serious adverse events
All SAEs (including death, irrespective of cause during the trial, regardless of their relationship to 
IMP, must be reported as soon as possible but no later than 24 hours after learning of the event. 
Before any trial-related procedure is performed, the trial site must be provided with contact details 
at the sponsor’s Drug Safety Department for this reporting.
The investigator must submit a report, called a safety reporting form, which includes a description 
of the event, the therapy instituted, and trial procedures. The following information should be 
communicated with the first notification of an SAE:
•
Trial identifier.
•
Subject’s identifier.
•
Subject’s date/year of birth (if available, see local data protection requirements) or age (at 
adverse event onset).
•
Subject’s sex.
•
First administration of IMP (date and time, if available).
•
Last administration of IMP (date and time, if available).
•
Adverse event verbatim term (specific diagnosis, if possible).
•
Adverse event onset (date and time, if available).
•
A brief description of the event, the course, and the countermeasures taken.
•
Intensity.
•
Seriousness criterion.
•
Outcome.
•
Concomitant medication at onset of the event and whether one of the concomitant 
medications is also suspected to have caused the event.
•
Relevant history/pre-existing medical conditions.
•
Investigator’s assessment of the relationship to IMPs.
•
Whether and when blinding was broken.
All additional information concerning the adverse event until trial termination or definite outcome 
must be communicated per follow-up report without delay.
The immediate and follow-up reports must only identify the subjects using the unique subject 
identifier. 
The investigator must comply with applicable regulatory requirement(s) related to the reporting of 
SAEs to the regulatory authorities and the relevant IECs or IRBs.
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Notification of serious adverse reactions
All suspected adverse drug reactions related to an IMP (the tested drugs and comparators) that 
occur in this trial, and that are both unexpected and serious are subject to expedited reporting.
Once a year throughout the clinical trial, the sponsor will provide the member states in whose 
territory the clinical trial is being conducted and the IECs with a listing of all suspected unexpected 
serious adverse reactions which have occurred over this period and a report of the subjects’ safety.
In addition, the sponsor will ensure that all reportable events are reported in compliance with 
applicable international and national regulatory requirements.
12.4.2
Vital signs
The vital signs comprise systolic and diastolic blood pressure, pulse rate, and respiratory rate.
Vital signs will be measured in a sitting position after resting for 10 minutes. While resting, the 
subject should not receive anything to drink or eat.
12.4.3
Body weight
Body weight will be measured in light clothes.
12.4.4
Twelve-lead electrocardiogram
All ECGs will be recorded in triplicate (3 readings in rapid succession no more than 2 minutes 
apart).
The times at which the ECGs were recorded will be documented in the eCRF.
The 12-lead ECG recordings will be performed after the subjects have been in a supine position for 
at least 10 minutes in a quiet environment without exciting distractions (e.g., television, video 
games). The recording should include a minimum of 5 heart cycles (beats).
Electrocardiographic parameters (heart rate; P, QRS, and T waves; PR, QT, and QTcF intervals), 
and waveform morphology will be evaluated by the investigator. The investigator will be 
responsible for determining the clinical relevance of any abnormality and deciding whether a 
subject can continue in the trial with the observed findings. The investigator will be required to 
comment any abnormalities with reference to any possible clinical relevance.
A central ECG reading facility will provide the results of the ECG interval measurements and an 
assessment and interpretation of any waveform abnormalities and other findings (e.g., conduction 
defects). The investigator will be informed of the results and must evaluate them in the context of 
the subject’s characteristics. The investigator will be required to comment any abnormalities with 
reference to any possible clinical relevance. The investigator will also make a decision whether the 
subject should continue in the trial or whether further ECGs or investigations should be performed 
to clarify and ensure the safety of the subject.
Electrocardiograms with poor quality tracings, artifacts or doubtful findings should be repeated, if 
possible.
For decisions relating to subject exclusion or discontinuation of IMP, the investigator’s initial 
evaluation will be used.
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The evaluation from the central ECG reading facility will be used for the assessment and analysis of 
ECG parameters and for evaluation of any tendency regarding changes in ECG parameters for the 
final integrated clinical trial report.
The ECG measurements and the findings, if any, from the central ECG evaluation together with the 
overall assessment of the clinical relevance by the investigator will be captured in the database.
The original ECG recordings will be kept at the trial site.
The ECG files including the waveforms and caliper placements will be provided electronically as 
xml files to the sponsor at the end of the trial.
12.4.5
Safety laboratory
Safety laboratory tests (except for urine dipsticks for urinalysis, semi-quantitative urinary ACR 
determination, urine drug testing, and urine pregnancy testing) will be performed by a central 
laboratory.
The use of any laboratory facility other than the designated laboratory for safety laboratory tests 
required by this protocol is not allowed. The only exception is in the case of an emergency where 
the investigator requires the results quickly.
A table of the reference ranges for each of the laboratory parameters measured with a description of 
the methods will be provided by the laboratory before the trial start and is to be filed in the 
investigator’s site file.
Changes in the reference ranges or in the methodology during the course of the trial are to be 
communicated by the laboratory to the sponsor who will inform the investigators.
The trial sites will be provided with a manual by the laboratory specifying the specimen collection, 
preparation, packaging, and transport of all safety laboratory tests required by this protocol.
Throughout the clinical part of the trial, the investigator must provide a comment in the eCRF 
regarding the clinical relevance of any laboratory values outside the sponsor-defined alert range.
Results for the laboratory parameters defined below will be sent electronically to the trial site and 
transferred electronically to the data management provider where these electronic data will be 
integrated into the clinical database. The clinical database will be transferred to the sponsor.
The following tests will be performed:
Hematology panel
Erythrocytes
Leukocytes (including basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils if a differential count is 
performed)
Hematocrit
Platelets
Hemoglobin
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Clinical chemistry panel 
Alanine aminotransferase
Magnesium
Albumin 
Parathyroid hormone a
Alkaline phosphatase 
Phosphate
Aspartate aminotransferase
Potassium
Bilirubin (total)
Protein (total)
Calcium (measured and albumin-corrected)
Sodium
Creatine kinase
Triacylglycerol lipase
Creatinine
Urea
Gamma glutamyl transferase
Uric acid
Glucose (non-fasted or fasted)
Vitamin D
Lactate dehydrogenase
a) Enrollment Visit only.
The eGFR will be calculated using the 2009 CKD-EPI creatinine equation (Levey et al. 2009).
Urinalysis panel
Dipstick
Semi-quantitative dipstick
Quantitative analysis
Bilirubin
Urinary albumin/creatinine ratio
Albumin (microalbumin)
Erythrocytes
Creatinine
Glucose
Calculated urinary albumin/creatinine ratio
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Urobilinogen
If the dipstick test is positive except for pH, glucose or ketones and erythrocytes/leukocytes in 
menstruating subjects, a microscopic examination of urine sediment will be performed to determine 
the presence of erythrocytes, leukocytes, epithelial cells, crystals, casts, bacteria, and other findings.
The number of samples and volume per sample collected from each subject for safety laboratory 
analysis are given in Table 3.
If laboratory values of liver parameters exceed pre-defined ranges (a combination of alanine 
aminotransferase and/or aspartate aminotransferase greater than 3 times the upper limit of normal 
and/or bilirubin greater than 2 times the upper limit of normal) after first application of IMP, a 
standard algorithm to detect and follow-up on potential severe cases of drug-induced liver injury 
will be applied (see Section 18.2).
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12.4.6
Physical examination
After treatment allocation, any clinically relevant changes from the previous visit for physical 
examination will be documented as adverse events.
12.4.7
Urine beta-human chorionic gonadotropin pregnancy test
Urine samples will be provided by women of child-bearing potential at the specified times and 
tested locally using a urine ß-HCG pregnancy dipstick test.
The results of the dipstick test will be directly entered into the eCRF.
Additional pregnancy tests to those specified may be performed if required by local law or 
regulations.
Pregnancy testing may be requested from the central laboratory.
12.5
Collection of plasma concentration data
12.5.1
Blood sampling for bioanalysis
Details of the blood sample collection times for plasma concentrations are given in the schedules of 
events (Section 1.7).
The exact sampling time must be recorded in the eCRF.
The blood samples for plasma concentrations will be collected via single venipuncture or an 
indwelling cannula. If required, a mandrin will be used to maintain the patency of the catheter for 
the blood sampling. Blood sampling must be performed from the contralateral arm to the one 
used for infusion or other appropriate location to avoid any possibility of contamination. 
Blood samples obtained during infusions must not be taken from the same access as used for 
IMP administration.
Further instructions for the blood sample collection and handling, labeling, and shipping are given 
in the laboratory manual, which will be supplied to the investigator.
The number of samples, volume per sample, and total blood volume collected are given in Table 3.
12.5.2
Bioanalytical assays
Plasma samples will be analyzed to determine concentrations of neridronic acid using a validated 
bioanalytical assay under the supervision of the department of pharmacokinetics at the sponsor.
Following completion of these assays, the residual samples will be retained until the end of the trial.
The bioanalytical report (PK1769A), including a description of the assay and a summary of the 
assay performance data, will be included in the final integrated clinical trial report.
12.6
Collection of pharmacodynamic data
12.6.1
Bone turnover markers
Details of the blood sample collection times for the bone turnover markers are given in the 
schedules of events (Section 1.7). Samples should be collected in the morning after an overnight 
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fast due to diurnal variation and effects of a meal. Serum concentrations will be determined for the 
following bone turnover markers:
•
Bone formation markers:
−
Procollagen type I amino-terminal propeptide.
−
Bone alkaline phosphatase.
•
Bone resorption marker:
−
C-terminal telopeptide of type I collagen.
Specific procedures for preparation of serum samples and storage and shipment will be provided to 
the sites.
12.7
Collection of markers for disease severity or progression of CRPS
12.7.1
Soluble interleukin-2 receptor (sIL-2R)
Details of the blood sample collection times for the analysis of sIL-2R are given in the schedules of 
events (Section 1.7).
Specific procedures for the preparation of the plasma samples and instructions for storage and 
shipment will be provided to the sites.
12.8
Collection of pharmacogenetic and omics data
Blood samples for storage and pharmacogenetic and omics testing will be collected into plastic 
ethylenediaminetetraacetic acid (EDTA) tubes from consenting subjects at the times given in the 
schedules of events (Section 1.7). The blood samples will be labeled with the trial code and subject 
number (and, if appropriate, using a bar code). They will not carry any personal identifier (i.e., 
single-coded data or double-coded data as described in ICH topic E15 2008).
The blood samples will initially be sent from the trial site to a temporary storage site qualified by 
the sponsor for short-term storage. The samples will then be transferred in batches from the 
temporary storage site to the bio-banking facility qualified by the sponsor for long-term storage.
Following extraction of DNA from the pharmacogenetic blood samples, the DNA will be stored in 
appropriate containers and labeled with a trial code and subject number (and, if appropriate, using a 
bar code). For omics, the plasma samples will be stored.
They will not carry any personal identifier (i.e., they will be double-coded data as described in ICH 
topic E15 2008). The DNA samples will be stored at the external bio-banking facility for up to 
15 years after completion of the trial (defined as the date of approval of the integrated clinical trial 
report in the sponsor’s document management system) to allow for pharmacogenetic testing. After 
15 years of storage, the DNA and plasma samples will be destroyed.
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12.9
Collection of health economics outcome and work productivity data 
(US sites only)
12.9.1
Work Productivity and Activity Impairment Questionnaire: CRPS
History of CRPS including impairments of personal activities, both work-related (e.g., 
absenteeism/presenteeism) and non-work-related will be captured using the WPAI: CRPS 
(Section 18.3.9).
The WPAI questionnaire is an instrument to measure impairments in both paid work and unpaid 
work (Reilly et al. 1993). It measures absenteeism and presenteeism as well as the impairments in 
unpaid activity because of health problems during the past 7 days.
The WPAI: CRPS will be assessed using the tablet computers maintained at the sites at the time 
points given in the schedules of events (Section 1.7).
12.9.2
Medical resources utilization and health economics data collection
Medical resource utilization and health economics data will include information regarding 
hospitalization, emergency room visits, nursing home stays, health care provider (other than trial 
investigator) contacts, home services, home help, and special devices used due to CRPS-related 
symptoms and pain. Data will be collected at the time points given in the schedules of events 
(Section 1.7).
The questions to be asked by the investigator are provided in Section 18.5.
The responses to the questions will be documented on paper and stored as part of the source data. 
Data will be transcribed into the eCRF by the investigator or delegated site staff.
12.10
Appropriateness of measurements
Efficacy assessments
As CRPS is a rare, poorly understood chronic pain syndrome condition with very few adequate and 
well-controlled trials having been conducted, the proposed outcome measures for this trial have not 
been formally validated in this population.
The efficacy assessments chosen for this trial reflect the core outcome measures for CRPS clinical 
trials (COMPACT). These were developed by an international consortium of patients, clinicians, 
researchers and industry representatives to develop and agree on a minimum core set of 
standardized outcome measures for use in future CRPS clinical trials in an adult population (Grieve 
et al. 2017). The key concepts identified were pain, disease severity, participation and physical 
function, emotional and psychological function, self-efficacy, catastrophizing and PGIC. The final 
core measurement set included the optimum generic or condition-specific patient-reported 
questionnaire outcome measures, which captured the essence of each domain.
Numerical rating scale for pain
The unidimensional 11-point NRS is a recommended method of assessing pain intensity in subjects 
with various types of chronic pain (CPMP/EWP/252/03 Rev. 1).
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On the basis of IMMPACT recommendations for core outcome measures in chronic pain studies, 
the 11-point NRS was chosen as the primary efficacy outcome measure (Dworkin et al. 2005). The 
NRS is a standard, widely used tool for the assessment of pain (Dworkin et al. 2008). Average, 
worst, and current pain intensity will be assessed.
For subject-reported outcomes captured electronically, the system will ensure data integrity by 
allowing only subjects to enter the data (electronic diary, tablet computer at the site). Electronic 
subject-reported outcome systems ensure that neither sponsors nor investigators can access and 
change the data, and subjects cannot enter data retrospectively or in advance, i.e., the timing of 
entries is controlled and compliance is enforced. Additionally, no data are lost because of illegible 
handwriting. As required by the FDA Guidance for Industry 2009 on the use of subject-reported 
outcomes, the database for the electronic patient-reported outcomes uses a regular back-up and does 
not allow access to unblinded data.
Subjects report little difficulty with electronic patient-reported outcome system procedures and are 
not unduly burdened by their use resulting in good reporting compliance (Stone et al. 2004).
Dynamic mechanical allodynia
Allodynia is a positive sign identified by physicians in about 70% of CRPS patients and a self-
reported symptom by almost 90% of the CRPS patients (Harden et al. 2010b). The DMA 
measurement is part of the Quantitative Sensory Testing protocol developed by the German 
Research Network on Neuropathic Pain as a comprehensive battery of sensory tests to quantify 
functions of the human somatosensory nervous system (Maier et al. 2010).
Pressure pain threshold
The PPT aims to quantify the mechanical deep somatic hyperalgesia in CRPS patients. Many 
patients with CRPS report pain in the depth of the limb rather than superficially in the skin, pointing 
to the importance of deep somatic structures such as bones, joints, tendons, and muscles in the 
pathophysiology of CRPS (Mainka et al. 2014).
Pain localized in the deep tissues occurs frequently in CRPS. In addition, hyperalgesia to blunt 
pressure over muscles is common in CRPS. The PPT over the thenar muscle provides 77% 
sensitivity and 63% specificity in identifying a patient with CRPS (cutoff 293 kPa; Mainka et al. 
2014).
Edema measurement - figure-of-eight method
Edema is a sign identified by physicians in about 65% of CRPS patients and a self-reported 
symptom by almost 90% of the CRPS patients (Harden et al. 2010b). Quantifications of edema are 
used to establish a baseline at the initial examination and to document changes in subject status. The 
figure-of-eight is a method of measuring edema by means of measuring tape and pre-defined 
anatomical landmarks. It demonstrated high intra-rater reliability, inter-rater reliability, and 
concurrent validity (Pellecchia 2003, Leard et al. 2004, dos Reis et al. 2004).
Active range of motion - goniometry
Decreased AROM is a sign identified by physicians in and a self-reported symptom by about 86% 
of CRPS patients (Harden et al. 2010b). The AROM is measured using an universal hand-held 
goniometer, based on the guidance recommended by the American Medical Association guidelines 
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and by the American Society of Hand Therapists’ clinical assessment recommendations. The 
AROM was applied for subjects with CRPS by Perez et al. 2003 and Oerlemans et al. 1998.
Possible threats to the reliability of the AROM measurements (more than one rater, [in]experience 
of the rater [unstructured] measurement protocols) have to be controlled for by using a rigid 
measurement protocol, valid and reliable measurement instruments, and, where possible, the same 
rater performing the initial and subsequent measurements for 1 subject (Perez et al. 2003).
CRPS Severity Score
The CRPS Severity Score has been shown to discriminate well between CRPS and non-CRPS 
patients and displayed strong associations with dichotomous CRPS diagnoses using both IASP 
diagnostic criteria and proposed revised criteria (Harden et al. 2010b). A higher CRPS Severity 
Score was associated with significantly higher clinical pain intensity, distress, and functional 
impairments, as well as greater bilateral temperature asymmetry and thermal perception 
abnormalities. Changes in the CRPS Severity Score show a strong correlation to changes seen in 
measures for depression and pain scores (Sayyad et al. 2011).
The following outcome measures selected for this trial were based on clinical outcome measures 
used in interventional trials in more common chronic pain conditions.
Patient Global Impression of Change
The 7-point PGIC is a subject-reported outcome measure tied to the conceptual framework of 
overall improvement. It is a recommended and responsive outcome domain for pain-related clinical 
trials (Dworkin et al. 2005, Farrar et al. 2001).
Patient Global Impression of Severity
The PGI-S is a global index that may be used to rate the severity of a specific condition (a single-
state scale). It is a simple, direct, easy-to-use scale that is intuitively understandable to clinicians 
(Yalcin et al. 2003).
EuroQol-5 dimension-5 level
The EQ-5D-5L health questionnaire is a generic health-related quality of life instrument developed 
by a multidisciplinary team of European researchers. It provides a simple descriptive profile and a 
single index value that can be used in the clinical and economic evaluation of health care and in 
population health surveys to assess health outcome from a wide variety of interventions. The EQ-
5D-5L is widely used in different countries by clinical researchers in a variety of therapeutic areas.
PROMIS-29 profile
The PROMIS is an existing item bank of patient-reported outcome measures (Cella et al. 2007). It is 
a National Institute of Health (United States of America) funded system, which provides 
psychometrically sound and validated patient-reported outcome measures. These can be used in a 
wide range of chronic conditions. The PROMIS is comprised of calibrated item banks to measure 
diverse health concepts such as pain, physical function and depression presented for each domain as 
individual items and/or instruments of various lengths. In addition, PROMIS includes several 
collections of items, termed profiles, which measure multiple domains.
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The PROMIS items can be compared directly with many standard instruments currently employed 
in clinical trials, such as the 36-item Short-Form Health Survey (SF-36) or Brief Pain Inventory 
(Choi et al. 2012).
The PROMIS-29 profile is recommended in COMPACT as a measurement tool for core outcome 
domains of depression, anxiety, physical function, pain interference, fatigue, sleep, and social 
participation, as well as an additional outcome measure for pain intensity (Grieve et al. 2017). For 
assessing the suicidal ideation, COMPACT recommends the supplementary use of the PROMIS-
EDDEP39.
Short-Form McGill Pain Questionnaire 2: 6 neuropathic items
The SF-MPQ-2 is a single measure of the major symptoms of both neuropathic and non-
neuropathic pain. It has excellent reliability and validity, and the results of both exploratory and 
confirmatory factor analyses provided support for 4 readily interpretable subscales: continuous pain, 
intermittent pain, predominantly neuropathic pain, and affective descriptors (Dworkin et al. 2009).
The COMPACT consortium recommends the assessment of pain qualities using the 6 neuropathic 
items from the SF-MPQ-2 as these were considered to capture the essential qualities with minimum 
patient burden (Grieve et al. 2017).
Pain Catastrophizing Scale
Trials in non-CRPS populations indicate catastrophizing is a prospective predictor of negative pain 
outcomes. The COMPACT consortium recommends the PCS be used to capture pain 
catastrophizing (Sullivan et al. 1995): a score of greater than 30 is thought to represent a 
problematic level of catastrophic thinking (Sullivan et al. 2009). Bean et al. (2016) reported the 
average PCS score at baseline was 22.0 in their sample of 66 patients diagnosed with CRPS within 
the previous 12 weeks, but underwent significant reduction to a mean score of 13.4 by 6 months as 
treatment progressed (p<0.001). This suggests pain catastrophizing as an important outcome and the 
PCS as a sensitive measurement tool.
Pain Self Efficacy Questionnaire
The PSEQ will be used to capture pain self-efficacy. The respondent considers how confident they 
are performing each activity, while taking their pain into account. This provides more clinically 
useful data than asking about performing an activity in isolation (Nicholas 2007). The accumulated 
evidence from a number of published trials and a conf rmatory analysis with a large cohort of 
heterogeneous chronic pain patients attending a pain management program provide support for the 
original psychometric properties of the PSEQ developed with a sample of chronic low back pain 
patients (Nicholas 2007).
Pharmacodynamic assessments
Bone turnover markers
The bone biomarkers CTX (for resorption) and BAP and PINP (for bone formation) have been 
selected in accordance with recommendations for the selection of these particular biomarkers in 
other bone diseases, including osteoporosis (Wheater et al. 2013; Vasikaran et al. 2011). Disordered
bone metabolism has been suspected in CRPS based on abnormalities observed on imaging (x-rays, 
bone densitometry and, in particular, bone scintigraphy using radiolabeled bisphosphonates). The 
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selected markers are known to be responsive to and associated with the mechanism of action of 
bisphosphonates.
Markers for disease severity or progression of CRPS
Soluble interleukin-2 receptor (sIL-2R)
Interleukin-2 (IL-2) is a cytokine crucially important in regulating activation, proliferation, and 
survival of different T-cell subsets. This effect of IL-2 is mediated through the IL-2 receptor which 
consists of the common γ-chain (CD132), a β-chain (CD122), and an α-chain (CD25). CD25 is 
strongly expressed on activated T-cells, which also secrete this molecule as a soluble variant 
(referred to as soluble IL-2 receptor; sIL-2R) from the cell membrane into the circulation.
According to Bharwani et al. 2017, plasma sIL-2R levels are significantly elevated in CRPS 
patients, indicating an increased T-cell activity in CRPS. This finding could point towards a T-cell-
mediated inflammatory process in CRPS and sIL-2R could be a potential new marker to determine 
inflammatory disease activity in CRPS.
Health economics outcome and work productivity data collection
Work Productivity and Activity Impairment Questionnaire: CRPS
The WPAI questionnaire is a well validated instrument to measure impairments in work and 
activities. It has been validated to quantify work impairments for numerous diseases such as asthma, 
psoriasis, irritable bowel syndrome, ankylosing spondylitis, Crohn’s disease, chronic non-malignant 
pain, low back pain, and neuropathic pain. In addition, the WPAI questionnaire has been used to 
compare work impairments between treatment groups in clinical trials or between subjects with 
different disease severity levels.
Medical resource utilization and health economics data
The data collected by means of this exploratory assessment will support determining the type and 
frequency of healthcare services used by CRPS patients. This information, correlated with 
corresponding costs, may be used in developing an evidence-based economic model.
12.11
Compliance
Compliance is the adherence to all requirements of the trial protocol.
Trial site compliance will be assured by the implementation of a quality system and the 
performance of a combination of trial site visits, training, and monitoring visits. Non-compliance 
should lead to prompt action by the sponsor to secure compliance.
Compliance of the subjects to record their pain intensity assessments in the electronic diary will be 
checked by the investigator at the respective visits. A non-compliant subject may be withdrawn 
from the trial at the discretion of the investigator.
Relevant deviations from the protocol will be documented and described in the integrated clinical 
trial report.
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13
DOCUMENTATION OF TRIAL DATA
The trial documentation must be adequate for the reconstruction of the trial.
13.1
Case report forms
Case report forms for each subject will be provided to the investigator by the sponsor in electronic 
format to document the trial data.
The investigator and personnel delegated the task will use eCRFs to record information required by 
the protocol.
All eCRF entries, corrections, and alterations will be made by the investigator or other authorized 
personnel under their supervision. Entries will be checked against appropriate source documents by 
authorized sponsor representatives as deemed appropriate in the monitoring guidelines.
The data collection will be done using a validated electronic eCRF system. The collected data will 
reside on servers of the eCRF provider. Entry, corrections and alterations of data within the system 
can only be performed by the investigator or other authorized personnel under their supervision and 
will be captured by the system’s audit trail.
Dedicated users (e.g., the investigator, designated persons at the trial site, authorized sponsor 
representatives, and from other parties involved, e.g., data management) will be trained and receive 
access rights according to their role in the trial. All users will have access to the system and be able 
to review their data on an ongoing basis.
After completion of the subject’s eCRF, the eCRF must be signed electronically by the investigator. 
With the investigator’s signature it is confirmed that the data in the eCRF are checked, complete, 
accurate, and in alignment with the source data. Changes to the eCRF after initial signing by the 
investigator need re-signing.
With database lock, the edit rights to the eCRFs will be removed but the investigator will retain 
access to view the eCRFs until receipt of a certified copy of all data captured for his or her subjects 
(site archive). This data will be delivered in a human readable form for retention in his or her files.
13.2
Subject-reported outcomes
Subject-reported outcomes will be collected using a validated electronic patient-reported outcome 
system including audit trail (electronic diary and site tablet computer).
The investigator will be trained on the use of the electronic patient-reported outcome system and the 
related oversight system. The oversight system will allow the investigator to review all data entered 
by the respective site subjects on an ongoing basis.
Subjects will receive a personal electronic diary at the trial site and will be instructed on how to use 
it.
The tablet computers will be kept at the trial site and subjects will be instructed on how to use it.
No queries will be issued to the investigator for these data, except for clarification of subject 
identifiers and any operational issues. No queries will be raised to the subject.
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With database lock, the writing access to the electronic patient-reported outcome system will be 
removed. The investigator will receive all data captured for his or her subjects, in a human readable 
form, on read-only media for his or her files. The information will be provided to the investigator 
prior to system decommissioning.
13.3
External data
Trial data not recorded in the eCRF or subject-reported outcome, but requested per protocol (e.g., 
safety laboratory data, ECG data) will be collected and validated via sponsor internal or external 
data providers. The data integration into the clinical data and respective quality control measures 
are described in the Data Management Plan.
13.4
Data management
Data management will be performed by sponsor personnel or by authorized sponsor representatives. 
Documentation of the responsibilities and delegation thereof will be maintained in the trial master 
file.
All aspects of the data management process, including data validation and query management, 
medical coding, handling of external data, data lock procedures are described in the Data 
Management Plan. Details on data validation are described in the Data Validation Plan.
13.5
Source data
Source data is defined by GCP as “all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies)”.
Source data comprise clinical documentation, data, and records (e.g., clinic/hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, and data and records arising from 
departments such as the pharmacy, laboratory, and medico-technical departments) that describe or 
record the methods, conduct, or results of the trial, the factors affecting the trial, and the actions 
taken.
All source data arising from the trial will be kept by the investigator, who must provide direct 
access for trial-related monitoring, audits, ethics committee review, and regulatory inspection.
In certain circumstances, data may only be recorded in the trial-specific eCRF and not in other 
documents. When this occurs, the eCRF is considered to be the source document. Data expected to 
be only recorded in the eCRF are race/ethnicity and sex.
The nature and location of all source data/clinical documentation will be identified and documented 
by the investigator to ensure that all sources of original data required to complete the eCRF are 
known to the sponsor and/or trial site personnel and are accessible for verification during trial-
related monitoring, audits, relevant IEC/IRB review, and inspections.
For subject-reported outcomes captured directly via the electronic patient-reported outcome system, 
source data is defined as the data residing in the vendor’s database.
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13.6
Investigator’s site file and the trial master file 
The principal investigator is responsible for the filing of all essential documents in an investigator’s 
site file. The sponsor is responsible for the timely filing of all essential documents in the trial master 
file. As applicable, these files must be available at monitoring visits and during audits or regulatory 
inspections.
After trial completion, the principal investigator must ensure that all source data/documentation 
related to the trial is recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation and verification. The principal investigator must take measures to prevent accidental 
or premature destruction of these documents.
The principal investigator must keep the investigator’s site file, the source data/documentation 
arising from the trial according to the prescribed record retention period in the country and/or 
according to the hospital policy, but at least until informed by the sponsor that the trial-related 
records are no longer required.
14
QUANTITATIVE ANALYSES
14.1
Statistical methods and sample size determination
14.1.1
Sample size rationale
The sample size rationale for the trial is provided in Section 1.5.1.
14.1.2
General description of statistical analyses
The statistical analysis of this trial will be planned, performed, and reported by sponsor personnel or 
by authorized sponsor delegates.
The data collected and derived for the trial will be presented in subject data listings.
Data collected in this trial will be summarized according to their nature as follows:
•
Continuous variables: arithmetic mean, standard deviation, minimum and maximum values, 
median and quartiles depending on the number of observations.
•
Categorical variables: absolute and relative frequencies. 
•
Time-to-event variables: Kaplan-Meier estimates together with the 95% confidence 
intervals and the hazard rate will be provided with the respective number at risk and the 
number censored at the relevant time points. In addition, the median time-to-event and its 
95% confidence interval will be presented.
All the statistical analyses will be performed by treatment group (and overall where appropriate).
Sites will be pooled by geographic region. Geographic regions will be defined as USA/Canada, 
Europe, and Other Regions (including Asia-Pacific and Australia/New Zealand).
The trial will be analyzed once all the data is cleaned and the database is locked.
Full details of the planned statistical analyses will be described in the trial statistical analysis plan.
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14.1.3
Analysis populations (analysis sets)
For the definition of analysis populations, please refer to Section 1.5.2.
14.1.4
Subject disposition
Subject disposition will be summarized descriptively for all enrolled subjects. Discontinuations will 
be summarized descriptively for all allocated subjects.
14.1.5
Analysis of demographic data and other baseline characteristics
Subject demographics and other baseline characteristics will be summarized descriptively by 
treatment group and overall for the Full Analysis Set and the Safety Set.
14.1.6
Concomitant medication and therapies
Concomitant medication and therapies will be summarized descriptively in the FAS and SAF with 
special focus on concomitant analgesic medication. Further summaries may be provided for 
specified therapies.
14.1.7
Analysis of efficacy data
All primary and secondary efficacy parameters will be summarized by descriptive statistics. The 
analysis of the primary efficacy endpoint will be performed on the Full Analysis Set. All other 
efficacy endpoints will be descriptively summarized in the Full Analysis Set. Confirmatory testing 
will be performed for the primary endpoint and for selected secondary endpoints. Further analyses 
may be done, including statistical hypothesis tests, but all analyses will be exploratory in nature and 
will not provide confirmatory evidence.
14.1.7.1
Analysis of the primary endpoint
See Section 1.2 for the definition of the primary endpoint.
14.1.7.1.1
Primary analysis
For the primary objective of the trial, the primary estimand is the difference in means of the primary 
efficacy endpoint of 400 mg intravenous neridronic acid compared to placebo for all allocated and 
treated subjects. This treatment policy or de facto estimand measures the effect of neridronic acid 
regardless of adherence to treatment or protocol.
The primary estimand will be estimated by the analysis of the primary efficacy endpoint for the Full 
Analysis Set. The primary analysis will fit an MMRM to the change from baseline in the average 
pain intensity scores from Week 1 to Week 12 recorded once daily in the electronic diary, including 
the covariate baseline pain intensity score, and the factors geographic region, week, treatment, and 
treatment-by-week interaction as fixed effects, and an unstructured covariance matrix to model the 
covariance structure of the repeated measurements.
The primary efficacy analysis will be performed using the contrast, i.e., the mixed model Wald test, 
of neridronic acid 400 mg versus placebo at Week 12 of the treatment, week and treatment-by-week 
interaction term of the mixed effects model described above. Model-based parameter estimates, 
standard errors, 95% confidence intervals, and p-values will be tabulated. This analysis will be 
performed using only the observed values without imputation of missing values.
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A descriptive summary of the weekly averages and the changes from baseline will be generated by 
treatment group. Graphical displays will be used if appropriate.
14.1.7.1.2
Sensitivity analysis
Additional sensitivity analyses will be performed to assess the robustness of primary analysis 
results. Sensitivity analyses will include the imputation of missing pain intensity scores using 
different PMMs.
14.1.7.2
Analysis of the secondary efficacy endpoints
All secondary efficacy endpoints will be analyzed for the Full Analysis Set.
Average pain intensity
The change from baseline in the average pain intensity, recorded on the tablet computer, will be 
analyzed with an MMRM, including the covariate baseline pain intensity score, and the factors 
geographic region, week, treatment, and treatment-by-week interaction as fixed effects, and subject 
as random effect. An unstructured covariance matrix will be used to model the covariance structure.
The analysis will be performed using the contrast, i.e., the mixed model Wald test, of 400 mg 
neridronic acid versus placebo at Week 26 of the treatment, week and treatment-by-week 
interaction term of the mixed effects model described above. Model-based parameter estimates, 
standard errors, 95% confidence intervals, and p-values will be tabulated. This analysis will be 
performed using the observed values without imputation of missing values.
Pain response to treatment
Pain response to treatment, defined as an at least 30% decrease from baseline in average pain 
intensity, recorded on the tablet computer, will be derived. If a subject shows a worsening or the 
pain intensity score for the respective visit is missing then the subject will be considered a pain non-
responder for the respective visit. A logistic regression model at Week 12 and Week 26 will be 
fitted to the data, including the covariate baseline pain intensity score, and the factors geographic 
region, and treatment as fixed effects. Model-based parameter estimates, standard errors, 95% 
confidence intervals, and p-values for the odds ratio at Week 12 and Week 26 between 400 mg 
neridronic acid and placebo will be tabulated.
The analysis of pain response to treatment will include a cumulative responder analysis at Week 12, 
Week 26, and Week 52, where responder rates will be calculated for different percentage thresholds 
for decrease from baseline in average pain intensity.
Dynamic mechanical allodynia
The change from baseline in the DMA will be analyzed using a similar model as for average pain 
intensity. Only subjects with allodynia at baseline, i.e., a DMA score greater than 0 on the 0 to 10 
NRS, will be included in the analysis.
Pressure pain threshold
The change from baseline in the ratio of the PPT in the affected limb to the PPT in the unaffected 
limb for the thenar muscle/abductor hallucis muscle will be analyzed using a similar model as for 
average pain intensity. Only subjects with deep somatic pain (PPT ! 300 kPa) in the affected limb at 
baseline will be included in the analysis.
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Edema
The change from baseline in edema will be analyzed using a similar model as for average pain 
intensity. Only subjects with presence of the CRPS sign “asymmetric edema” at baseline will be 
included in the analysis.
14.1.7.3
Handling of missing data
Diligent attempts will be made to limit the amount of missing data in the primary efficacy endpoint.
Efforts will be made to follow-up subjects who discontinue treatment and to collect the primary 
efficacy endpoint for the statistical analysis.
The primary analysis using the MMRM is based on the MAR assumption. For the treatment policy 
or de facto estimand, the MAR assumption is justified for neridronic acid owing to the long half-life 
in bone and the anticipated persistent effect over the 12-week trial period. It can be assumed that the 
effect of neridronic acid continues after the treatment period is completed, and it also persists after 
the treatment period regardless of trial completion or early discontinuation. Therefore, the response 
of discontinued subjects will not change if the subjects continue to receive the stable therapy that 
they receive during the 12-week trial period up to Visit 8. If subjects change their treatment after 
discontinuation from the trial, it is nevertheless reasonable to assume that their response is not 
significantly altered as there are currently no established effective treatments. Hence, the MAR 
assumption is considered a plausible missingness mechanism for the primary estimand in the case 
of neridronic acid.
The MAR assumption cannot be verified based on data observed in the trial. Deviations from MAR 
cannot be excluded and several plausible MNAR assumptions will be investigated to assess their 
impact. MNAR assumptions will be defined via PMMs specifying the distribution of missing 
values, e.g., for subjects discontinuing before the end of the trial. Plausible PMMs for the primary 
estimand are PMI and the delta shift method. 
Placebo multiple imputation is a reference-based approach based on the copy reference method. It 
models the means of missing values in the active arm based on the means observed in the placebo 
arm (reference arm). The method assumes that the response of discontinued subjects in the active 
arm gradually approaches the response in the placebo arm and eventually no effect of neridronic 
acid persists after a subject discontinues. For neridronic acid this appears conservative in light of the 
anticipated persistent effect.
The delta shift method models the means of missing values in the active arm by adding a pre-
specified value Δ to the observed means in the active arm. The method includes a tipping point 
analysis, which is defined as the delta that must be added in order to overturn conclusions from the 
primary analysis from statistically significant to statistically insignificant. The method assumes that 
discontinued subjects in the active arm have higher pain compared to subjects who stay in the trial. 
Again this seems conservative if persistence of effect can be assumed for neridronic acid.
Overall, the 2 PMMs can be considered more conservative than MAR because they model missing 
pain intensity scores in the active arm using higher mean values than the means actually observed, 
whereas the placebo arm is not changed. In this way, neridronic acid is effectively penalized under 
these assumptions. 
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In summary, for neridronic acid the MAR assumption seems to be the most plausible missingness 
assumption for analyses estimating the primary estimand. It will be supplemented by sensitivity 
analyses based on MNAR assumptions representing plausible and reasonably conservative 
deviations from MAR.
14.1.7.4
Confirmatory testing strategy for secondary endpoints
A confirmatory testing procedure will be used for testing of the superiority of neridronic acid 
400 mg versus placebo with respect to the primary and selected secondary efficacy endpoints 
(change from baseline to Week 26 in the average pain intensity, change from baseline to Week 12 
in the pain intensity level of DMA, change from baseline to Week 12 in the PPT ratio, and change 
from baseline to Week 12 in the ratio of figure of eight measurements).
First, the primary endpoint will be tested at a one-sided level α = 2.5%. If the first test is statistically 
significant, the 4 secondary endpoints will be tested in a second stage.
To control for the family-wise type I error rate at the one-sided 2.5% level, a hybrid Hochberg-
Hommel step-up procedure (hybrid-0 procedure in Gou et al. 2014) will be applied. The testing 
procedure uses the ordered p-values p(1) ≥ p(2) ≥ p(3) ≥  p(4). At first, if the largest p-value p(1) ≤ α, 
then all 4 hypotheses are rejected. Otherwise the associated null hypothesis H(1) is accepted and 
testing proceeds to the next step. In general, at Step i = 2,..4, if  p(i)  ≤ ciα, then any hypothesis with 
p-value ≤ diα will be rejected and testing stops; otherwise the null hypothesis H(i) and testing 
continues at the next step. At Step 4, the null hypothesis H(4) is rejected if p(4) ≤ α/4; otherwise H(4)
is accepted. The constants used in the testing procedure are defined by ci = (i+1)/(2i) and di = 1/i
and are given in the table below.
I
1
2
3
4
ci
1
3/4
2/3
5/8
di
1
1/2
1/3
1/4
This semiparametric multiple testing procedure controls the family-wise error rate in the strong 
sense if the test statistics follow a multivariate normal distribution with non-negative correlation 
coefficients (Gou et al. 2014) which can be assumed for the investigated 4 efficacy endpoints.
14.1.7.5
Subgroup analyses
Subgroup analyses may be done if appropriate and will be specified in the statistical analysis plan.
14.1.8
Analysis of safety data
The analysis of safety data will be performed using the Safety Set.
14.1.8.1
Adverse events
A definition of adverse event is given in Section 12.4.1.
The original terms recorded in the eCRF to identify adverse events will be coded using the most 
recent version of the Medical Dictionary for Regulatory Activities (MedDRA) at the time of 
database lock.
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Adverse events are only considered treatment emergent adverse events (TEAEs) if they start after 
first administration of IMP. All adverse events occurring in a subject administered a trial treatment 
and which do not necessarily have a causal relationship with this treatment will be defined as 
TEAEs. In addition, pre-treatment adverse events which worsen during the treatment periods are 
also considered TEAEs.
Treatment emergent adverse events will be summarized.
An overview of the number and percentage of subjects with at least 1 TEAE, serious TEAEs, non-
serious TEAEs, unexpected TEAEs, related TEAEs, related serious TEAEs, TEAEs leading to 
discontinuation from IMP, TEAEs leading to discontinuation from the trial, and deaths will be 
created.
The number and percentage of subjects with adverse events and the number and percentage of 
events will be summarized by System Organ Class and Preferred Term for TEAEs, serious TEAEs, 
non-serious TEAEs, and related TEAEs.
Additional summaries by intensity, causal relationship, outcome, countermeasure, time to onset, 
duration, and expectedness will be provided.
Subjects with SAEs and subjects with adverse events leading to trial/treatment discontinuation will 
additionally be listed.
The distribution of time to onset of any TEAE will be summarized using time-to-event methods if 
applicable. A graphical display using Kaplan-Meier methods displaying subjects at risk per time 
point will also be produced.
14.1.8.2
Safety laboratory values, vital signs, 12-lead ECG
Safety laboratory values, vital signs, and 12-lead ECG (including changes from baseline as 
applicable) will be descriptively summarized per visit.
Baseline will be the value collected on Day 1 (Visit 2) prior to first administration of IMP.
A listing of subjects with values outside the sponsor-defined alert ranges will be provided.
The ECG printouts will be interpreted by the investigator as “normal”, “abnormal, but clinically not 
relevant”, or “abnormal and clinically relevant”. Results from this interpretation will be reported in 
subject data listings.
14.1.9
Analysis of neridronic acid plasma concentration data
Pharmacokinetic concentrations will be analyzed in the Pharmacokinetic Set. Descriptive statistics 
and optionally graphs of the observed neridronic acid plasma concentrations at the planned time 
windows will be created. Owing to the sparse sampling and the random time points, no derivation 
and analysis of non-compartmental pharmacokinetic parameters is foreseen.
14.1.10
Analysis of pharmacodynamic data
Bone turnover marker values will be descriptively summarized by parameter for the 
Pharmacodynamic Set.
Baseline is defined by the value on Day 1 (Visit 2).
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14.1.11
Analysis of health economics outcome and work productivity data
Health economics and work productivity data will be summarized descriptively for the Full 
Analysis Set.
14.1.12
Analysis of soluble interleukin-2 receptor
Analysis of sIL-2R concentrations will be summarized descriptively for the Safety Set.
14.1.13
Interim analysis
The interim analysis for the trial is described in Section 1.5.3.7.
14.2
Pharmacometric analyses
Modeling and simulation analyses will be performed by sponsor personnel or by authorized sponsor 
delegates.
A previously developed population pharmacokinetics model will be updated using the plasma 
concentrations-time data for neridronic acid.
An exploratory evaluation of the potential exposure-response relationships between neridronic acid 
exposure levels and the primary efficacy endpoint will be performed.
Based on the graphical exploration outcome, further investigations will be performed if deemed 
necessary.
Population pharmacokinetics and exposure-response modeling will be performed by means of a 
nonlinear mixed effect modeling approach as implemented in NONMEM®.
Details will be described in pharmacometric analysis plans.
The results of any analyses will be reported in a pharmacometric report, i.e., separately from the 
integrated clinical trial report.
14.3
Analysis of the trial – pharmacogenetic and omics analysis
The pharmacogenetic testing will be performed on blood samples from this trial after the clinical 
data has been unblinded if a safety signal is seen, or a decision is made to analyze the relationship 
between single-nucleotide polymorphisms of genetically polymorphic genes and their 
corresponding proteins and pathways with pharmacokinetics or pharmacodynamics of the 
compound.
The objectives and methods of the pharmacogenetic testing will be described in a pharmacogenetic 
testing plan, which will be finalized before the pharmacogenetic testing starts. The genotyping 
study plan describing technical details of the pharmacogenetic testing will be provided by the 
genetic CRO. The results of the pharmacogenetic and omics testing will be reported by the CRO in 
a separate study report.
The pharmacogenetic data generated will not be used to make a diagnosis about the health of a 
subject. 
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The results of the pharmacogenetic and omics testing for individual trial subjects will not be 
supplied to the trial subject or to the subject’s physician.
14.4
Ad hoc analyses
Data collected in this trial may be used for ad hoc medical or scientific analyses, e.g., analyses to 
explore pharmacokinetic/pharmacodynamic relationships. These analyses will be planned, 
performed, and reported by sponsor personnel or by authorized sponsor delegates in accordance 
with sponsor SOPs.
15
QUALITY SYSTEM, AUDIT, AND INSPECTION
15.1
Quality system
The sponsor is responsible for implementing and maintaining quality assurance and quality control 
systems with written SOPs.
15.2
Data quality assurance
The accuracy and reliability of the trial data will be assured by careful CRO/investigator selection 
and oversight by the performance of a combination of trial site visits, training, monitoring visits, 
remote verification by the sponsor or appropriate use of electronic tools by the trial site, data 
cleaning, and audits.
Trial site monitoring as defined in GCP will be performed by sponsor personnel or by authorized 
sponsor delegates at pre-defined intervals depending on the progress of the trial.
Corrections, amendments, or clarifying statements resulting from monitoring visits should be made 
by the investigator where necessary. 
Appropriate checking against source documents must be done by the sponsor. 
Audits as defined by GCP should be performed for this trial. The auditors will be independent of the 
trial and its performance.
15.3
Inspections 
The principal investigator, any investigator(s), the sponsor, or personnel at other establishments, 
must cooperate with any inspection of the documents, facilities, records, and other resources 
deemed appropriate by the inspecting authorities to be related to the trial and that may be located at 
the trial site, at the sponsor, or at other establishments. 
The sponsor must be notified as soon as possible about any upcoming regulatory authority 
inspection.
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16
GENERAL CONDITIONS AND AGREEMENTS
16.1
Insurance
If required by applicable regulatory requirements, the sponsor will arrange suitable insurance for the 
subjects included in this trial and provide the investigator with the relevant terms and conditions of 
this insurance. The investigator must inform all subjects about this insurance and (if requested) be 
prepared to explain the relevant terms and conditions of this insurance to the subject.
If changes to the trial are implemented after the initial insurance was arranged, e.g., due to protocol 
amendments, the sponsor will notify the insurance company of these changes in accordance with 
the insurance conditions. If changes to insurance arise, the sponsor will inform the investigators 
who will then inform their subjects about relevant changes.
16.2
Legal regulations
This trial will be carried out in compliance with any applicable regulatory requirements.
Before initiating the trial, if required by the applicable regulatory requirements, the sponsor or its 
authorized legal representative and/or the investigator will submit any required documents to the 
appropriate authorities for review, acceptance, and/or permission to begin the trial. 
16.3
Contracts
Specific contracts between the relevant parties, i.e., between the investigator/other parties at the trial 
sites and the sponsor or its local offices or CRO or its affiliates authorized by the sponsor, will be 
used to set out any arrangements on delegation and distribution of tasks and obligations and, if 
appropriate, on financial matters. This protocol and other documentation may serve as the basis of 
such contracts. In case of discrepancies with other contracts, the provisions of the protocol prevail.
In addition, responsibility for insurance or indemnity to cover any liability of the investigator that 
may arise directly or indirectly from the investigator’s participation in the trial will be specified in a 
contract between the investigator and sponsor, if applicable.
16.4
Subject data and data protection
Subject trial data will be stored in a manner maintaining confidentiality in accordance with 
applicable regulatory requirements.
The investigator must ensure that any documents or data given to the sponsor or authorized sponsor 
representatives do not contain information that would affect the confidentiality of the subject’s
identity.
The investigator will obtain permission for direct access to original subject data from the subject as 
part of the written informed consent procedure (see Section 4.2). This gives permission to examine, 
analyze, verify, and reproduce any records and reports that are important to the evaluation of the 
trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor personnel or its 
representatives, and auditors) with direct access must take all reasonable precautions within the 
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constraints of the applicable regulatory requirement(s) to maintain the confidentiality of the 
subject’s identity and sponsor’s proprietary information.
16.5
Public disclosure
The results of this trial will be publically disclosed in accordance with the sponsor’s disclosure 
policy, the European Federation of Pharmaceutical Industries and Associations (EFPIA) Principles 
for Responsible Clinical Trial Data Sharing and applicable regulatory guidance (e.g., on 
ClinicalTrials.gov).
The results (or parts thereof) of this trial may be published as a publication (e.g., journal 
publication) or at a congress (e.g., as a poster or presentation). The sponsor reserves the right to 
review any proposed full publication or poster or presentation of the results of this trial by the 
coordinating or other investigator before they are submitted for publication or public disclosure.
Neither the sponsor nor the coordinating investigator has the right to prohibit publication or public 
disclosure. Publication or public disclosure can be postponed for patent purposes.
16.6
Trial results reporting
A final report integrating clinical, pharmacokinetic, pharmacodynamic, and statistical results will be 
prepared by the sponsor. The international coordinating investigator will approve the final report on 
behalf of the participating investigators.
The sponsor will provide the competent authority/ies and relevant IECs or IRBs with a summary of 
the trial results in accordance with applicable regulatory requirements. 
All principal investigators will be provided with a summary of the trial results.
All entered subjects will be provided access to a summary of the trial results in a lay-understandable 
form.
16.7
Approval
16.7.1
Sponsor 
This protocol has been approved in accordance with sponsor SOPs. 
16.7.2
Coordinating investigator
This protocol has been approved by the international coordinating investigator.
17
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Neuropathic Pain (DFNS), v2.1, 2010. Accessed at http://www.neuro.med.tumuenchen. 
de/dfns/pdfs/QST-Investigators_brochure_Version_2_1_final_english_2010_07_09.pdf.
Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, et al. IOM 
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18
APPENDIX
18.1
List of potentially important medical concepts – classified by System 
Organ Class
Blood and lymphatic system disorders
Agranulocytosis
Aplastic anaemia
Blast cell proliferation 
(myeloproliferative and 
lymphoprolipherative disorders)
Bone marrow depression
Disseminated intravascular 
coagulation (DIC)
Haemolytic anaemia 
Histiocytosis
Loss of anticoagulation control 
Pancytopenia 
Splenic haemorrhage, infarction or 
thrombosis
Thrombocytopenia (<30000)
Thrombotic thrombocytopenic 
purpura
Cardiac disorders
Angina unstable
Atrial flutter
Atrioventricular block complete
Cardiac arrest
Cardiac failure acute
Cardiac fibrillation
Cardiac tamponade 
Cardiogenic shock 
Cardiomyopathy acute 
Coronary artery spasm
Cor pulmonale decompensated
Myocardial infarction
Torsade de pointes
Ventricular fibrillation
Ventricular tachycardia 
Ear and labyrinth disorders
Deafness
Vestibular ataxia
Endocrine disorders
Adrenocortical insufficiency acute
Eye disorders
Cataract/lens opacity
Glaucoma
Keratitis/corneal opacification
Macular degeneration 
Optic neuropathy, atrophy 
Papilloedema 
Ptosis 
Retinal artery/vein occlusion 
Retinitis 
Scotoma
Sudden visual loss
Uveitis
Vitreous detachment
Gastrointestinal disorders
Colitis haemorrhagic
Gastric ulcer haemorrhage
Gastric ulcer perforation
Haematemesis
Haemoperitoneum
Ileus 
Intestinal ischaemia 
Intestinal perforation 
Melaena 
Mesenteric occlusion 
Mesenteric vein thrombosis
Pancreatitis
Peritonitis
General disorders and administration site conditions
Malignant hyperthermia
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Hepatobiliary disorders
Hepatic failure
Hepatitis fulminant
Hepatic necrosis
Hepatorenal syndrome
Portal hypertension
Reye’s syndrome
Immune system disorders
Amyloidosis
Anaphylactic reaction
Anaphylactic shock
Graft versus host disease
Infections and infestations
Endotoxic shock
Sepsis
Toxic shock syndrome
Transmission of an infectious agent 
via a medicinal product
Injury, poisoning and procedural complications 
Transplant failure
Wound dehiscence
Metabolism and nutrition disorders
Diabetic coma
Failure to thrive 
Hypercalcaemia (CTC IV)
Hyperkalaemia (CTC IV)
Hypocalcaemia (CTC IV)
Hypokalaemia (CTC IV)
Lactic acidosis
Porphyria
Shock hypoglycaemic 
Tetany
Musculoskeletal and connective tissue disorders
Aseptic necrosis bone
Fracture pathological 
Muscle necrosis 
Osteomalacia 
Rhabdomyolysis
Systemic lupus erythematosus
Systemic sclerosis
Nervous system disorders
Amnesia
Anticholinergic syndrome
Aphasia
Cerebral oedema
Chorea
Coma
Convulsions
Demyelination
Encephalitis
Encephalopathy 
Epilepsy
Guillain-Barré syndrome
Hydrocephalus
Intracranial haemorrhage
Meningitis 
Multiple sclerosis
Myasthenia gravis
Myelitis
Neuroleptic malignant syndrome
Opisthotonus
Paralysis
Paresis
Parkinson’s syndrome
Serotonin syndrome
Stroke
Tunnel vision
Pregnancy, puerperium and perinatal conditions
Abortion
Eclampsia
Intra-uterine death
Psychiatric disorders
Anorexia nervosa
Delirium
Drug abuse
Drug dependence
Homicidal ideation
Intentional misuse
Self-injurious ideation/attempt
Suicidal ideation/attempt
Suicide completed
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Renal and urinary disorders
Anuria
Goodpasture’s syndrome
Haemolytic uraemic syndrome
Nephritis/nephritic syndrome
Nephrotic syndrome
Oliguria
Renal failure acute
Renal tubular necrosis
Urinary obstruction/retention
Reproductive system and breast disorders
Metrorrhagia/uterine haemorrhage
Priapism
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
Adult respiratory distress syndrome 
Alveolitis allergic
Asphyxia
Bronchospasm
Laryngeal oedema
Pulmonary fibrosis
Pulmonary haemorrhage
Pulmonary infarction
Pulmonary vasculitis
Respiratory arrest
Status asthmaticus
Pulmonary oedema
Skin and subcutaneous tissue disorders
Angioneurotic oedema
Erythema nodosum 
Pemphigus
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Vascular purpura
Vascular disorders
Acute circulatory failure 
Embolism
Malignant hypertension
Necrosis ischaemic
Thrombosis
Status: Dec 2017
CTC = Common Toxicity Criteria also referred to as the Common Terminology Criteria for Adverse Events (CTCAE).
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18.2
Algorithm for follow-up investigation of potential or suspected cases 
of drug-induced liver injury
If alanine aminotransferase or aspartate aminotransferase is >3 x the upper limit of normal, repeat 
the lab test within 48 hours to 72 hours. The test should be performed for aspartate 
aminotransferase, alanine aminotransferase, creatine kinase, total, direct and indirect bilirubin, 
alkaline phosphatase, lipase and gamma glutamyl transferase.
If alanine aminotransferase or aspartate aminotransferase is >3 x the upper limit of normal, 
(confirmed by retesting), and total bilirubin is ! 2 x the upper limit of normal, the investigator and 
the sponsor should discuss the following recommendations:
•
Initiate a close observation of the subject/patient. 
•
Repeat testing of alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, total, direct and indirect bilirubin, creatine kinase, gamma glutamyl 
transferase, international normalized ratio, eosinophilic granulocytes and lipase 2 times to 
3 times weekly. 
•
Decrease the frequency of retesting to once a week or less if abnormalities stabilize or if the 
IMP has been discontinued.
If aspartate aminotransferase or alanine aminotransferase is >3 x the upper limit of normal and total 
bilirubin is >2 x the upper limit of normal, the investigator and the sponsor should discuss following 
recommendations:
•
Repeat testing of alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, total, direct and indirect bilirubin, creatine kinase, gamma glutamyl 
transferase, international normalized ratio, eosinophilic granulocytes and lipase. 
•
Consult a hepatologist/gastroenterologist who must then conduct an obligatory abdominal 
ultrasound and other examinations (e.g., liver biopsy) as necessary. 
•
Obtain more detailed history of symptoms (fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia [>5%]). 
•
Obtain history of concomitant medications, including herbal drugs, alcohol use or other 
drugs of abuse. 
•
As appropriate, conduct laboratory investigations for other possible causes of liver injury. 
Testing can be discussed with the sponsor.
18.3
Subject-reported outcomes
The subject-reported outcomes provided in the following sections are validated English samples.
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18.3.1
Patient Global Impression of Change
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18.3.2
Patient Global Impression of Severity
Please choose the response below that best describes the severity of your CRPS symptoms over the 
past week:
˜
None
˜
Mild
˜
Moderate
˜
Severe
˜
Very severe
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18.3.3
EuroQol-5 dimension-5 level
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18.3.4
PROMIS-29 profile version 2.0
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18.3.5
PROMIS-EDDEP39
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18.3.6
Short-form McGill Pain Questionnaire 2: 6 neuropathic pain items
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18.3.7
Pain Catastrophizing Scale
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18.3.8
Pain Self Efficacy Questionnaire
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18.3.9
Work Productivity and Activity Impairment Questionnaire: CRPS
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18.4
Signs and symptoms of CRPS
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18.5
Health Economics Outcome Questionnaire (sample)
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19
PROTOCOL AMENDMENTS
19.1
Protocol Amendment 01
Amendment rationale
The principal changes in this amendment are based on FDA feedback received in September 2018
as well as feedback from ECs, IRBs, and other regulatory authorities. The following changes have 
been implemented:
•
Addition of weekly pain intensity assessments after Week 12 using an electronic diary.
•
Clarification of concomitant analgesic medication use as a (non-objective related) outcome.
•
Simplification of the description of “other data to be collected that are not directly 
attributed to or considered as an endpoint” (there was no change to the planned assessments 
or evaluations).
•
Removal of specification of male contraception in inclusion criterion 6.
•
Clarification in exclusion criterion 1 that the quoted eGFR and ACR thresholds refer to 
severe renal impairment.
Minor inconsistencies have also been corrected.
Detailed description of changes
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
In the table below, deleted text is crossed out and new text is highlighted using italics.
Changes to this protocol include:
Formerly read:
Now reads: 
Section 1.2: Trial objectives, endpoints, and outcomes
Section 1.5.3: Statistical methods and analysis
[…]
All efficacy and safety endpoints evaluated during 
Treatment Period B and Follow-up Period 2…
[…]
All efficacy and safety data evaluated during Treatment 
Period B and Follow-up Period 2…
Section 1.2: Trial objectives, endpoints, and outcomes
To assess the efficacy of neridronic acid in subjects with 
CRPS
•
Change from baseline to Week 52 in average 
pain intensity recorded on the tablet computer.
•
Change from Week 26 to Week 52 in average 
pain intensity recorded on the tablet computer.
•
Pain response to treatment, defined as at least 
50% decrease from baseline in the average 
pain intensity at Week 52, based on pain 
intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 
50% decrease from Week 26 in the average 
pain intensity at Week 52, based on pain 
All efficacy assessments will be evaluated for the time 
points indicated in the schedules of events.
To assess the efficacy of neridronic acid in subjects with 
CRPS
•
Change from baseline in average pain intensity 
recorded on the tablet computer.
•
Change from Week 26 in average pain 
intensity recorded on the tablet computer.
•
Pain response to treatment, defined as at least 
50% decrease from baseline in the average 
pain intensity, based on pain intensity 
recordings on the tablet computer.
•
Pain response to treatment, defined as at least 
50% decrease from Week 26 in the average 
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Changes to this protocol include:
Formerly read:
Now reads: 
intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 
50% decrease from baseline in the average 
pain intensity at Week 12, based on pain 
intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 
50% decrease from baseline in the average 
pain intensity at Week 26, based on pain 
intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 
30% decrease from baseline in the average 
pain intensity at Week 52, based on pain 
intensity recordings on the tablet computer.
•
Pain response to treatment, defined as at least 
30% decrease from Week 26 in the average 
pain intensity at Week 52, based on pain 
intensity recordings on the tablet computer.
•
Change from baseline to Week 12 in pain 
intensity scores determined using worst and 
current pain ratings recorded daily in the 
electronic diary.
pain intensity, based on pain intensity 
recordings on the tablet computer.
•
Pain response to treatment, defined as at least 
30% decrease from baseline in the average 
pain intensity, based on pain intensity 
recordings on the tablet computer.
•
Pain response to treatment, defined as at least 
30% decrease from Week 26 in the average 
pain intensity, based on pain intensity 
recordings on the tablet computer.
•
• Change from baseline in pain intensity scores 
determined using worst and current pain 
ratings recorded daily in the electronic diary.
•
Change from baseline to Week 26 in worst and 
current pain intensity ratings, recorded on the 
tablet computer.
•
Change from baseline to Week 52 in worst and 
current pain intensity ratings, recorded on the 
tablet computer.
•
Change from Week 26 to Week 52 in worst 
and current pain intensity ratings, recorded on 
the tablet computer.
•
Change from baseline to Week 6, Week 26, 
Week 36, and Week 52 in the pain intensity 
level of DMA.
•
Change from baseline to Week 6, Week 26, 
Week 36, and Week 52 in PPT ratios.
•
Change from baseline to Week 6, Week 26, 
Week 36, and Week 52 in the ratio of the 
figure of eight measurements of the affected 
limb versus the unaffected limb.
•
Change from baseline to Week 6, Week 12, 
Week 26, Week 36, and Week 52 in the active 
range of motion (AROM) ratio (affected limb 
and unaffected limb) measured in the hand or 
foot, respectively.
•
Change from baseline to Week 12, Week 26, 
and Week 52 in the CRPS Severity Score.
•
Patient Global Impression of Change (PGIC) at 
•
Change from baseline in worst and current pain 
intensity ratings, recorded on the tablet 
computer.
•
Change from Week 26 in worst and current 
pain intensity ratings, recorded on the tablet 
computer.
•
Duration of effect based on average pain 
intensity recordings in the electronic diary.
•
Change from baseline in the pain intensity 
level of DMA.
•
Change from baseline in PPT ratios.
•
Change from baseline in the ratio of the figure 
of eight measurements of the affected limb 
versus the unaffected limb.
•
Change from baseline in the active range of 
motion (AROM) ratio (affected limb and 
unaffected limb) measured in the hand or foot, 
respectively.
•
Change from baseline in the CRPS Severity 
Score.
•
Patient Global Impression of Change (PGIC).
•
Patient Global Impression of Severity (PGI-S).
•
Change from baseline in the EuroQoL-5 
Dimension-5 level (EQ-5D-5L) index score 
and the health-related visual analog scale 
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Changes to this protocol include:
Formerly read:
Now reads: 
Week 6, Week 12, Week 16, Week 22, Week 
26, Week 28, Week 36, and Week 52.
•
Change from baseline to Week 6, Week 12, 
Week 16, Week 22, Week 26, Week 28, 
Week 36, and Week 52 in the Patient Global 
Impression of Severity (PGI-S).
•
Change from Week 26 to Week 52 in the PGI
S.
•
Change from baseline to Week 12 and 
Week 26 in the EuroQoL-5 Dimension-5 level 
(EQ-5D-5L) index score and the health-related 
visual analog scale (VAS) score.
•
Change from baseline to Week 52 in the EQ
5D 5L index score and the health related visual 
analog scale score.
•
Change from Week 26 to Week 52 in the EQ-
5D-5L index score and the health-related visual 
analog scale score.
•
Change from baseline to Week 6, Week 12, 
Week 26, Week 28, Week 36, and Week 52 in 
the responses to questions on the following 
questionnaires (recorded on the tablet 
computer):
−
Patient-Reported Outcomes Measurement 
Information System (PROMIS®)-29 
profile version 2.0 (PROMIS-29 profile) 
(sub-scores: physical function, anxiety, 
depression, fatigue, sleep disturbance, 
social roles and activities, and pain 
interference). The change from baseline to 
Week 16 and Week 22 will be assessed 
for question number 29, GLOBAL07 
only.
−
Question EDDEP39 of the PROMIS Item 
Bank version 1.0 Emotional Distress 
Depression (PROMIS EDDEP39).
−
The 6 neuropathic pain items of the Short-
Form McGill Pain Questionnaire 2 (SF-
MPQ-2) (single items and the combined 
score).
−
Pain Catastrophizing Scale (PCS).
−
Pain Self Efficacy Questionnaire (PSEQ).
(VAS) score.
•
Change from Week 26 in the EQ-5D-5L index 
score and the health-related VAS score.
•
Change from baseline in the responses to 
questions on the following questionnaires 
(recorded on the tablet computer):
−
Patient-Reported Outcomes Measurement 
Information System (PROMIS®)-29 
profile version 2.0 (PROMIS-29 profile) 
(sub-scores: physical function, anxiety, 
depression, fatigue, sleep disturbance, 
social roles and activities, and pain 
interference). The change from baseline to 
Week 16 and Week 22 will be assessed 
for question number 29, GLOBAL07 
only.
−
The 6 neuropathic pain items of the Short-
Form McGill Pain Questionnaire 2 (SF-
MPQ-2) (single items and the combined 
score).
−
Pain Catastrophizing Scale (PCS).
−
Pain Self Efficacy Questionnaire (PSEQ).
•
Response to Question EDDEP39 of the 
PROMIS Item Bank version 1.0 – Emotional 
Distress – Depression (PROMIS-EDDEP39) 
(recorded on the tablet computer).
•
Concomitant analgesic medication use.
Section 1.3.1: Inclusion criteria
6. […] Highly effective methods of contraception must 
be used for at least 1 month prior to Visit 2 and for the 
duration of the trial.
Male subjects must use condom and spermicide during 
6. […] Highly effective methods of contraception must 
be used for at least 1 month prior to Visit 2 and for the 
duration of the trial.
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intercourse and must take care that the female sexual 
partner uses at least 1 additional method of contraception 
with a low failure rate defined as above, starting with 
Visit 2 until at least 4 weeks after the last IMP infusion.
Section 1.3.2: Exclusion criteria
1. Evidence of renal impairment…
[…]
2. Serum calcium or magnesium outside of the central 
laboratory’s reference range, based on central safety 
laboratory data obtained prior to Visit 2 (a single repeat 
laboratory test is allowed)
[…]
5. Subjects receiving medications with a known risk of 
torsades de pointes within 7 days prior to allocation. 
Subjects receiving selective serotonin re-uptake inhibitor 
antidepressants (e.g., citalopram, escitalopram) are 
eligible if the QT interval values do not meet the 
exclusion criteria, the medication was started at least 
1 month prior to allocation , the dose is stable, and the 
dose is anticipated to remain stable throughout the trial.
[…]
17. Participation in another investigational drug trial 
within 3 months prior to Visit 1, or any previous trial 
involving neridronic acid, with the exception of subjects 
participating in KF7013 01 who were assigned to 
placebo and did not receive neridronic acid.
1. Evidence of severe renal impairment…
[…]
2. Serum calcium or magnesium outside of the central 
laboratory’s reference range, based on central safety 
laboratory data obtained prior to Visit 2 (2 repeat 
laboratory tests are allowed);
[…]
5. Subjects receiving medications with a known risk of 
torsades de pointes within 7 days prior to allocation. 
Subjects receiving selective serotonin re-uptake inhibitor 
antidepressants (e.g., citalopram, escitalopram) are 
eligible if the QT interval values do not meet the 
exclusion criteria, the medication was started at least 
1 month prior to Visit 1, the dose is stable, and the dose 
is anticipated to remain stable throughout the trial.
[…]
17. Participation in another investigational drug trial 
within 3 months prior to Visit 1, or any previous trial 
involving neridronic acid.
Section 1.3.3: Criteria to continue into Treatment Period B
Up to 2 unscheduled retesting visits (with a minimum 
interval of 3 days) for serum calcium and/or vitamin D 
levels can be performed before Visit 11 if the scheduling 
and time window of Visit 11 is not affected.
[…]
− Evidence of renal impairment
[…]
− Serum calcium outside of the central laboratory’s 
reference range, despite appropriate supplementation 
between Visit 10 and Visit 11, based on the last central 
safety laboratory data obtained prior to Visit 11. Two
repeat laboratory tests are allowed.
− Vitamin D deficiency prior to IMP re-allocation, 
defined as a 25(OH)D level less than 30 ng/mL (75 
nmol/L), based on the last central safety laboratory data
obtained prior to Visit 11, i.e., inability to normalize 
25(OH)D levels to at least 30 ng/mL (75 nmol/L) despite 
appropriate supplementation between Visit 10 and Visit 
11. Two repeat laboratory tests are allowed.
In case of any safety laboratory retesting, the scheduling 
and time window of Visit 11 must not be affected..
[…]
− Evidence of severe renal impairment
[…]
− Serum calcium or magnesium outside of the central 
laboratory’s reference range, despite appropriate 
supplementation between Visit 10 and Visit 11, based on 
the last central safety laboratory data obtained prior to 
Visit 11. One repeat laboratory test is allowed.
− Vitamin D deficiency prior to IMP re-allocation, 
defined as a 25(OH)D level less than 30 ng/mL 
(75 nmol/L), based on the last central safety laboratory 
data obtained prior to Visit 11, i.e., inability to normalize 
25(OH)D levels to at least 30 ng/mL (75 nmol/L) despite 
appropriate supplementation between Visit 10 and 
Visit 11. Two repeat laboratory tests are allowed (with a 
minimum interval of 3 days).
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Section 1.4.1: Investigational medicinal products
Section 10.2: Administration of investigational medicinal products
CKD-EPI Stage 3a (eGFR 45 mL/min/1.73 m2 to 
<60 mL/min/1.73 m2)
6 mL of solution from a single vial (corresponding to 
neridronic acid 75 mg) will be diluted in 500 mL normal 
saline and administered at each treatment visit, resulting 
in a total dose of 300 mg neridronic acid or matching 
placebo.
CKD-EPI Stage 3b (eGFR 30 mL/min/1.73 m2 to 
<45 mL/min/1.73 m2)
5 mL of solution from a single vial (corresponding to 
neridronic acid 62.5 mg) will be diluted in 500 mL 
normal saline and administered at each treatment visit, 
resulting in a total dose of 250 mg neridronic acid or 
matching placebo.
CKD-EPI Stage 3a (eGFR 45 mL/min/1.73 m2 to 
<60 mL/min/1.73 m2)
6 mL of solution from a single vial (corresponding to 
neridronic acid 75 mg) will be diluted in 500 mL normal 
saline and administered by slow intravenous infusion 
(240 minutes [maximum 260 minutes]) at each treatment 
visit, resulting in a total dose of 300 mg neridronic acid 
or matching placebo.
CKD-EPI Stage 3b (eGFR 30 mL/min/1.73 m2 to 
<45 mL/min/1.73 m2)
5 mL of solution from a single vial (corresponding to 
neridronic acid 62.5 mg) will be diluted in 500 mL 
normal saline and administered by slow intravenous 
infusion (240 minutes [maximum 260 minutes]) at each 
treatment visit, resulting in a total dose of 250 mg 
neridronic acid or matching placebo.
Section 1.4.2: Prior/concomitant medications or therapies
A subject who does not take prescription analgesics is 
permitted to participate if considered stable and 
anticipated to be able to remain off prescription 
analgesics for the duration of the trial, up to and 
including Visit 8 at a minimum. Over-the-counter 
analgesics must also be recorded in the electronic case 
report form (eCRF) and remain stable throughout the 
trial
[…]
The concomitant medication must be documented in the 
eCRF and the sponsor  must be notified.
A subject who does not take prescription analgesics but 
does take over-the-counter analgesics is permitted to 
participate if considered stable and anticipated to be able 
to continue taking only over-the-counter and non-
prescription analgesics up to and including Visit 8 at a 
minimum. Over-the-counter analgesics must remain 
stable throughout the trial
[…]
The concomitant medication must be documented in the 
eCRF and the sponsor or sponsor’s representative (i.e., 
medical monitor) must be notified.
Section 1.4.2.1: Forbidden concomitant medications
[…]
• Concomitant administration of non-steroidal anti-
inflammatory drugs or any other agents with the 
potential to interfere with the assessment of potential 
changes in renal function (e.g., angiotensin converting 
enzyme inhibitors) until 2 weeks after the last IMP 
administration per treatment period, unless subjects are 
receiving a stable dose for at least 1 month prior to 
Visit 1. Non-steroidal anti-inflammatory drugs should 
not be used to alleviate the symptoms of the acute phase 
reaction and are forbidden 24 hours before and 10 hours 
after each IMP administration.
[…]
• Concomitant administration of non-steroidal anti-
inflammatory drugs or any other agents with the 
potential to interfere with the assessment of potential 
changes in renal function (e.g., angiotensin converting 
enzyme inhibitors) until 2 weeks after the last IMP 
administration per treatment period, unless subjects are 
receiving a stable dose for at least 1 month prior to 
Visit 1. Non-steroidal anti-inflammatory drugs should 
not be used to alleviate the symptoms of the acute phase 
reaction.
Section 1.5.3.1: Primary endpoint
Section 14.1.7.1.1: Primary analysis
The primary analysis will fit an MMRM to the change 
The primary analysis will fit an MMRM to the change 
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from baseline in the average pain intensity scores from 
Week 1 to Week 12 recorded once daily in the electronic 
diary, including the covariate baseline pain intensity 
score, and the factors geographic region, week, 
treatment, and treatment-by-week interaction as fixed 
effects, and subject as random effect. An unstructured 
covariance matrix will be used to model the covariance 
structure.
from baseline in the average pain intensity scores from 
Week 1 to Week 12 recorded once daily in the electronic 
diary, including the covariate baseline pain intensity 
score, and the factors geographic region, week, 
treatment, and treatment-by-week interaction as fixed 
effects, and an unstructured covariance matrix to model 
the covariance structure of the repeated measurements.
Section 1.5.3.2: Secondary efficacy endpoints
Section 14.1.7.2: Analysis of the secondary efficacy endpoints
Pain response to treatment
[…]
A logistic regression model will be fitted to the data, 
including the covariate baseline pain intensity score, and 
the factors geographic region, week, treatment, and 
treatment by week interaction as fixed effects.  Model-
based parameter estimates, standard errors, 95% 
confidence intervals, and p-values for the odds ratio at 
Week 12 and Week 26 between 400 mg neridronic acid 
and placebo will be tabulated.
Pain response to treatment
[…]
A logistic regression model at Week 12 and Week 26 will 
be fitted to the data, including the covariate baseline pain 
intensity score, and the factors geographic region and 
treatment as fixed effects. Model-based parameter 
estimates, standard errors, 95% confidence intervals, and 
p-values for the odds ratio at Week 12 and Week 26 
between 400 mg neridronic acid and placebo will be 
tabulated.
Section 1.7.1: Visit 1 to Visit 10
Dispense/collect electronic diary q [“X” at Visit 8 
deleted]
Training and compliance assessment for electronic diary
[…]
aa) Edema will only be measured in subjects reporting 
asymmetric edema as part of the assessment of the signs 
and symptoms of CRPS at baseline. The AROM will 
only be measured in subjects reporting decreased AROM 
as part of the assessment of the signs and symptoms of 
CRPS at baseline.
b) Infusion visits should be separated by 3-day intervals
to the extent possible (i.e., Day 1, Day 4, Day 7, and 
Day 10). Infusion visits on consecutive days are not 
allowed. The full dosing period should not exceed 21 
days
[…]
c) Visit 8 must not occur prior to Day 85 in order for the 
subjects to have complete electronic diary data through 
Week 12 for the calculation of the primary endpoint.
[…]
m) For women of child-bearing potential, a negative 
dipstick urine pregnancy test result must be obtained 
prior to each infusion.
[…]
q) The electronic diary is to be returned at Visit 8 or at 
Dispense electronic diary q
Training and compliance assessment for electronic diary 
[“X” added at Week 16 and Week 22] [Footnote “bb” 
added at Visit 1 and footnote “cc” added at Visit 8]
[…]
aa) Edema will only be measured in subjects reporting 
asymmetric edema as part of the assessment of the signs 
and symptoms of CRPS at baseline (Visit 2). The AROM 
will only be measured in subjects reporting decreased 
AROM as part of the assessment of the signs and 
symptoms of CRPS at baseline (Visit 2).
b) Infusion visits should be separated by 3-day intervals 
to the extent possible (i.e., Day 1, Day 4, Day 7, and 
Day 10). Infusion visits on consecutive days are not 
allowed. The full dosing period must not exceed 21 days
[…]
bb) Compliance assessment for electronic diary not 
required at Visit 1.
c) Visit 8 must not occur prior to Day 85 in order for the 
subjects to have complete electronic diary data through 
Week 12 for the calculation of the primary endpoint.
cc) Training on electronic diary as, from Week 12, the 
electronic diary will ask for weekly assessments of pain 
intensity.
[…]
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the Early Termination Visit…
m) For women of child-bearing potential, a negative 
dipstick urine pregnancy test result must be obtained 
prior to each infusion. Additional pregnancy tests to 
those specified may be performed if required by local 
law or regulations.
[…]
q) The electronic diary is to be returned at Visit 17 or at 
the Early Termination Visit…
Section 1.7.2: Visit 11 to Visit 17
Row added for “Training and compliance assessment for electronic diary” at Visit 11 to Visit 17
Row added to “Collect electronic diary” at Visit 17
b) […]The full dosing period should not exceed 21 days
[…]
i) For women of child-bearing potential, a negative 
dipstick urine pregnancy test result must be obtained 
prior to each infusion.
[…]
q) … Subjects who do not meet the criteria due to a pain 
intensity value of less than 4 will not enter Treatment 
Period B, but will continue with the Follow-up Period 2.
[…]
t) Edema will only be measured in subjects reporting 
asymmetric edema as part of the assessment of the signs 
and symptoms of CRPS at baseline. The AROM will 
only be measured in subjects reporting decreased AROM 
as part of the assessment of the signs and symptoms of 
CRPS at baseline.
u) The blood sample for omics testing will be collected 
in consenting subjects.
b) […]The full dosing period must not exceed 21 days
[…]
i) For women of child-bearing potential, a negative 
dipstick urine pregnancy test result must be obtained 
prior to each infusion. Additional pregnancy tests to 
those specified may be performed if required by local 
law or regulations.
[…]
q) … Subjects who do not meet the criteria to continue 
into Treatment Period B will continue with the Follow-
up Period 2.
[…]
t) Edema will only be measured in subjects reporting 
asymmetric edema as part of the assessment of the signs 
and symptoms of CRPS at baseline (Visit 2). The AROM 
will only be measured in subjects reporting decreased 
AROM as part of the assessment of the signs and 
symptoms of CRPS at baseline (Visit 2).
u) The blood sample for omics testing will be collected 
in consenting subjects.
v) No training needed at Visit 17.
Section 3.1: Abbreviations
eGFR
Estimated glomerular filtration rate
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
Section 8.2: Benefit/risk analysis
The trial population described in this protocol will 
consist of subjects with a diagnosis of CRPS, with onset 
of symptoms within the last 2 years, and who are 
medically stable and in stable follow-up therapy for 
CRPS for at least 1 month.
Subjects will continue to receive stable therapy for 
CRPS. Additional pain medication may be prescribed in 
the event of severe pain flare, with notification of the 
sponsor.
The trial population described in this protocol will 
consist of subjects with a diagnosis of CRPS, with onset 
of symptoms within the last 2 years, and who are 
medically stable and in stable follow-up therapy for 
CRPS for at least 1 month prior to allocation.
Subjects will continue to receive stable therapy for 
CRPS. Additional pain medication may be prescribed in 
the event of severe pain flare, with notification of the 
sponsor or sponsor’s representative (i.e., medical 
monitor).
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[…]
Acute phase reaction
The most common side effects associated with parenteral 
administration of aminobisphosphonates are flu-like 
symptoms, commonly referred to as “acute phase 
reaction” (Reid et al. 2010; Silverman et al. 2011). 
Symptoms include fever, myalgia, fatigue, headache, 
diarrhea, arthralgia, muscle pain, and bone pain.
[…]
As there are currently no Food and Drug Administration 
(FDA) approved treatments for CRPS…
[…]
Acute phase reaction
The most common side effects associated with parenteral 
administration of aminobisphosphonates are flu-like 
symptoms, commonly referred to as “acute phase 
reaction” (Reid et al. 2010; Silverman et al. 2011). 
Symptoms include fever, myalgia, fatigue, headache, 
diarrhea, arthralgia, and bone pain.
[…]
As there are currently no FDA or EMA approvals for
specific pharmacological treatments for CRPS…
Section 9.3.2: Subject discontinuation from the IMP
Table 2: Reasons for permanent and temporary 
discontinuation of subjects from IMP
[…]
Evidence suggestive of a possible change in renal 
function:
[…]
• A persistent increase of urinary ACR based on values 
>300 mg/g (quantitative urinary albumin and creatinine 
data from the central laboratory), and ≥150 mg/g 
(quantitative urinary albumin and creatinine data from 
the central laboratory) from urine samples obtained at 
least 1 week apart.
[…]
• A persistent eGFR <30 mL/min/1.73 m2 based on 
repeated quantitative data from the central laboratory, 
with blood and urine samples obtained at least 1 week 
apart.
[…]
a) Not applicable if no eGFR value after first IMP 
administration is available.
Table 2: Reasons for permanent and temporary 
discontinuation of subjects from IMP
[…]
Test results suggestive of a possible change in renal 
function:
[…]
• A persistent urinary ACR based on an initial value 
>300 mg/g (semi-quantitative dipstick or quantitative 
urinary albumin and creatinine data from the central 
laboratory) and on a second value ≥150 mg/g 
(quantitative urinary albumin and creatinine data from 
the central laboratory) from urine samples obtained at 
least 1 week apart.
[…]
• A persistent eGFR <30 mL/min/1.73 m2 based on 
repeated quantitative data from the central laboratory, 
with urine samples obtained at least 1 week apart.
[…]
a) Not applicable if no eGFR value after first IMP 
administration is available. For both treatment periods, 
the last value observed prior to first IMP application in 
Treatment Period A will be used for calculating the 
decrease in eGFR.
Section 11.1.1.1: Visit 1 (Day -60 to Day -8)
• Training and compliance assessment for electronic 
diary.  
• Training for electronic diary.  
Section 11.1.2: Treatment Period A
Section 11.1.4.2: Treatment Period B
[…]
The full dosing period should not exceed 21 days from 
the first infusion…
[…]
The full dosing period must not exceed 21 days from the 
first infusion…
Section 11.1.3.3: Visit 8 (Day 85 [Week 12]; +7 days)
• Collect electronic diary.
• Training on electronic diary as, from Week 12, the 
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electronic diary will ask for weekly assessments of pain 
intensity.
Section 11.1.3.4: Visit 9 (Day 113 [Week 16]; ±4 days)
Section 11.1.3.5: Visit 10 (Day 155 [Week 22]; ±4 days)
Section 11.1.4.1: Visit 11 (Day 183 [Week 26]; +7 days)
Section 11.1.4.2.1: Visit 12 (Day 186; ±1 day) - only subjects receiving a second treatment course
Section 11.1.4.2.2: Visit 13 (Day 189; ±1 day) - only subjects receiving a second treatment course
Section 11.1.4.2.3: Visit 14 (Day 192; ±1 day) - only subjects receiving a second treatment course
Section 11.1.4.3: Visit 15 (Day 197 [Week 28]; +7/-2 days) - only subjects receiving a second treatment course
Section 11.1.4.4: Visit 16 (Day 253 [Week 36]; ±7 days) - for all subjects
• Check trial discontinuation criteria…
• Compliance assessment for electronic diary.
• Check trial discontinuation criteria…
Section 11.1.4.1: Visit 11 (Day 183 [Week 26]; +7 days)
Subjects who do not meet the criteria due to a pain 
intensity value of less than 4 will not enter Treatment 
Period B, but will continue with the Follow-up Period 2.
Subjects who do not meet the criteria to continue into
Treatment Period B will continue with the Follow-up 
Period 2.
Section 11.1.4.5: Visit 17 (Day 365 [Week 52]; +7 days) - for all subjects
• Complete the assessment of the signs and symptoms of 
CRPS.
• Complete the assessment of the signs and symptoms of 
CRPS.
• Compliance assessment for electronic diary.
• Collect electronic diary.
Section 11.3.2: Meals and fluid intake restrictions
Visits 2, 6, 7, 8, 10, 15, 16, and 17 should be attended in 
a fasting state (at least 8 hours).
Light meals are allowed after sampling for bone turnover 
markers and may be provided before and/or after IMP 
infusions…
Visits 2, 6, 7, 8, 10, 15, 16, and 17 should be attended in 
a fasting state (at least 8 hours).
Light meals are allowed after sampling for bone turnover 
markers and may be provided before, during, and/or after 
IMP infusions…
Section 12.2.2: Prior and concomitant medication or therapies
All medication requiring prescriptions (including oral 
contraceptives), over-the-counter medication (including 
herbals and vitamins), and therapies (including medical 
devices and therapies such as e.g., massage or cognitive 
behavioral therapy) used within 3 months prior to 
enrollment and up to the end of the trial must be 
recorded in the eCRF. Any change in dosage, regimen, 
frequency, or route, must be recorded in the eCRF as a 
new entry.
All medication requiring prescriptions (including oral 
contraceptives), over-the-counter medication (including 
herbals and vitamins), and therapies (including medical 
devices and therapies such as e.g., massage or cognitive 
behavioral therapy) used within 3 months prior to 
enrollment and up to the end of the trial must be 
recorded in the eCRF. All failed CRPS medication must 
be added in the eCRF (including medications stopped 
before 3 months prior to enrollment). Any change in 
dosage, regimen, frequency, or route, must be recorded 
in the eCRF as a new entry.
Section 12.2.3.1: Diagnosis of CRPS
Distal to mid-limb involvement (typically hand or foot), 
with or without proximal spread, should be present.
[…]
Diagnosis of CRPS involving an atypical body part 
Distal to mid-limb involvement (typically hand or foot), 
with or without proximal spread, must be present.
[…]
Ongoing, disproportionate pain and a lack of other 
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(e.g., trunk, breasts, pelvic regions, lower back, face) 
is not permitted for this trial.
diagnosis that better explains the signs and symptoms 
must also be confirmed at the Enrollment Visit.
Diagnosis of CRPS involving an atypical body part 
(e.g., trunk, breasts, pelvic region, lower back, face, 
shoulder, or hip) is not permitted for this trial.
Section 12.2.4.2: Urine drugs of abuse test
[…]
Subjects who are receiving stable doses of prescribed 
medications containing amphetamines, benzodiazepines 
or opioids will not be excluded from the trial even if the 
test is positive.
[…]
Subjects who are receiving stable doses of prescribed 
medications containing amphetamines, benzodiazepines, 
cannabinoids, or opioids will not be excluded from the 
trial even if the test is positive.
Section 12.3.1.1: Electronic diary
Subjects will be asked to record their average, worst, and 
current CRPS-related pain intensity once daily in the 
electronic diary (in the evening), using an 11-point NRS 
(from 0 = “no pain” to 10 = “pain as bad as you can 
imagine”) starting at Visit 1 and continuing until Visit 8. 
Worst and average pain intensity will be for a 24-hour 
recall period.
Subjects will be asked to record their average, worst, and 
current CRPS-related pain intensity once daily in the 
electronic diary (in the evening), using an 11-point NRS 
(from 0 = “no pain” to 10 = “pain as bad as you can 
imagine”) starting at Visit 1 and continuing until Visit 8. 
Worst and average pain intensity will be for a 24-hour 
recall period.
After Visit 8 up to Visit 17, subjects will be asked to 
record their average, worst, and current CRPS-related 
pain intensity once weekly in the electronic diary (in the 
evening) using the same 11-point NRS and a 24-hour 
recall period.
Section 12.3.2: Dynamic mechanical allodynia
[…]
A value of “10” corresponds to the individual maximum 
pain imaginable. The tactile stimulus is tested 5 times. 
The degree of pain…
[…]
A value of “10” corresponds to the individual maximum 
pain imaginable. The tactile stimulus is tested 5 times. If 
the subject reports a value of “10”, then no further test 
will be performed for the respective visit. The degree of 
pain…
Section 12.3.5: Active range of motion measurement
For subjects having decreased AROM at baseline 
(diagnosed based on clinical judgment; sign “Motor 
abnormalities” ticked “yes”, sub-category “decreased 
AROM” ticked “yes” on the CRPS Severity Score at 
baseline), both…
For subjects having decreased AROM at baseline 
(diagnosed based on clinical judgment; sign “Motor 
abnormalities” ticked “yes”, sub-category “decreased 
AROM” ticked “yes” on the CRPS Severity Score at 
baseline [Visit 2]), both…
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SAP_000.pdf: 
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ID: 
 
 
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.0
1350646
Statistical Analysis Plan for the Pooled KF7013-02 & KF7013-04
Interim Analysis for Futility
Safety Approval
02-Jul-2018 14:50 GMT+02
Clinical Approval
02-Jul-2018 16:35 GMT+02
Biostatistics Approval
03-Jul-2018 10:41 GMT+02
NCT03530345 and NCT03560986


Confidential
Page 1 of 8
SDR-SAP-INTR-02
CONFIDENTIAL
No part of this document may be passed on, reproduced or published without written 
permission of Grünenthal
STATISTICAL ANALYSIS PLAN
POOLED INTERIM ANALYSIS
FOR KF7013-02 AND KF7013-04
Version
Date
DMS version number
Original
28 Jun 2018
1.0
This document was approved according to the sponsor’s standard operating procedures.
DMS version: 
 
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Statistical Analysis Plan
Pooled Interim Analysis KF7013-02 and KF7013-04
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TABLE OF CONTENTS
1
INTRODUCTION
3
2
OBJECTIVES OF ANALYSIS
3
3
TRIAL DESIGNS
4
4
ENDPOINT CRITERIA
4
5
SUBJECT POPULATION
4
5.1
Interim Analysis Set
4
6
STATISTICAL METHODS
4
6.1
Source of data
4
6.2
Changes in analysis
5
6.2.1
Description of SAP amendments
5
6.3
Description of analysis
5
6.3.1
Handling of missing values
5
6.3.2
Subject disposition
5
6.3.3
Premature terminations
5
6.3.4
Subject demographics
6
6.3.5
Baseline characteristics
6
6.3.6
Previous and concomitant medication
6
6.3.7
Subject medical history
6
6.3.8
Drug exposure
6
6.3.9
Analysis of efficacy
6
6.3.10
Analysis of adverse events
7
6.3.11
Analysis of laboratory parameters
8
6.3.12
Analysis of vital signs
8
6.3.13
Analysis of further safety parameters
8
7
STATISTICAL OUTPUT DOCUMENTATION
8
8
CODING
8
9
STATISTICAL SOFTWARE
8
10
REFERENCES
8
11
APPENDIX
8
11.1
Reference ranges for laboratory parameters
8
11.2
Sponsor defined ranges for laboratory parameters
8
11.3
Table shells, figure shells, and listings
8
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Statistical Analysis Plan
Pooled Interim Analysis KF7013-02 and KF7013-04
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LIST OF ABBREVIATIONS
Abbreviation
Explanation
ADaM
Analysis Data Model
CRPS
Complex Regional Pain Syndrome
IMP
Investigational medicinal product
MAR
Missing at Random
MMRM
Mixed Model Repeated Measurements
NRS
Numeric Rating Scale
SAP
Statistical analysis plan
SAS
Statistical analysis software
SDTM
Study Data Tabulation Model
1
INTRODUCTION
This statistical analysis plan (SAP) includes definitions and analysis details for the pooled interim 
analysis of the 2 Phase III neridronic acid trials, KF7013-02 and KF7013-04 in accordance with the 
protocols, both dated 14 Mar 2018. The analysis will be performed by an independent statistician in 
accordance with this SAP and the associated charter.
2
OBJECTIVES OF ANALYSIS
The primary objective of the 2 trials is to demonstrate the superior efficacy of a cumulative dose of 
400 mg intravenous neridronic acid versus placebo for the treatment of complex regional pain 
syndrome (CRPS)-related pain. The primary endpoint is the change from baseline to Week 12 in the 
average pain intensity score (weekly average of pain values recorded daily in the electronic diary).
An interim analysis is planned after a combined total of approximately 80 subjects in the 2 Phase III 
trials (KF7013-02 and KF7013-04) have completed Week 12 of treatment and the required data is 
available in the databases. The interim analysis is for futility only and will be non-binding. The 
futility criterion will be based on the unblinded comparison of the primary endpoint and will be 
calculated using identical methods as for the final analysis. If the observed difference in the means 
of neridronic acid and placebo (μ400 - μ0) is ≥-0.3 points on the Numeric Rating Scale (NRS), the 
null hypothesis will not be rejected and the recommendation will be to stop both trials. 
The interim analysis will be performed by an independent statistician not otherwise involved in the 
conduct of the trials and the result will only state the recommendation to stop or continue the 
Phase III program. No unblinded information will be disseminated to the trial teams. Pending 
recruitment rates of both trials, it may be decided to forgo the interim analysis or conduct it at a 
different point in time. Recruitment will continue during the interim analysis. 
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Pooled Interim Analysis KF7013-02 and KF7013-04
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3
TRIAL DESIGNS
Both trials are identical in design and are multi-site, randomized, double-blind, placebo-controlled, 
2-arm, Phase III trials of intravenous neridronic acid in subjects with CRPS. The trials consist of 
2 treatment periods. Treatment Period A will be double-blind, whereas Treatment Period B will be 
open-label. There will be an Enrollment Period (lasting up to 60 days) followed by Treatment 
Period A (consisting of 4 infusions over 10 days), and a Follow-up Period 1 (lasting from Visit 6 
[Week 2] up to Visit 11 [Week 26]. At Visit 11 (Week 26), subjects not meeting the pre-specified 
criteria to continue into Treatment Period B will continue in the Follow-up Period 2 until Visit 17 
(Week 52). The interim analysis will only include data collected up to Visit 8 (Week 12) of the 
double-blind phase. 
Subjects will be randomized to 1 of the 2 treatment groups in a 1:1 ratio stratified by geographic 
region. The 2 trials will have no overlap in sites (i.e., a site can participate in only one trial). 
4
ENDPOINT CRITERIA
The interim analysis will be limited to the average pain intensity score rated on a 11-point NRS
(from 0 = “no pain” to 10 = “pain as bad as you can imagine”) reported once daily (in the evening, 
24-hour recall) in an electronic diary. The change from the baseline phase (Day -7 to Day -1) to 
Week 12 will be analyzed.
5
SUBJECT POPULATION
5.1
Interim Analysis Set
The Interim Analysis Set includes the first 80 subjects allocated in the combined trials KF7013-02 
and KF7013-04 who have at least 1 investigational medicinal product (IMP) administration, and 
who have completed the Week 12 visit, or discontinued from the trial prematurely before Week 12.
6
STATISTICAL METHODS
The statistical methods applied will be similar to those planned for the individual trials. Further 
details can be found in the SAPs of the KF7013-02 and KF7013-04 trials. 
6.1
Source of data
Relevant data (demographics, disposition, CRPS history, and pain diary) of subjects included in the 
Interim Analysis Set will be cleaned and a formal locked snapshot for each trial will be made 
available. Required Study Data Tabulation Model (SDTM) and Analysis Data Model (ADaM)
domains will be prepared for each of the 2 trials. Subsequently, these will be pooled for the 
statistical analysis. 
The randomization list for the Interim Analysis Set will be provided to the independent statistician 
separately. The independent statistician will merge the randomization code into the datasets before
conducting the analysis. The unblinded datasets will be kept at the independent statistician’s secure 
location until the closure of the trials.
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6.2
Changes in analysis 
6.2.1
Description of SAP amendments
Not applicable.
6.3
Description of analysis 
In the following sections, a detailed description of variables and statistical methods used in the 
interim analysis is given. All presentations will be by treatment group and overall, for both trials 
combined and repeated for each trial separately. 
6.3.1
Handling of missing values
Unless otherwise specified in this SAP, missing values will not be imputed. For the handling of 
missing or incomplete dates, please refer to the trial SAPs. 
For the primary analysis of the Interim Analysis, few missing values are expected. Moreover, for 
the treatment policy or de facto estimand of the primary efficacy analysis, the Missing at Random 
(MAR) assumption is justified for neridronic acid owing to the long half-life in bone and the 
anticipated persistent effect over the 12-week trial period. It can be assumed that the effect of 
neridronic acid continues after the treatment period is completed, and it also persists after the 
treatment period regardless of trial completion or early discontinuation. Therefore, the response of 
discontinued subjects will not change if the subjects continue to receive the stable therapy that they 
receive during the 12-week trial period. If subjects change their treatment after discontinuation from 
the trial, it is nevertheless reasonable to assume that their response is not significantly altered as 
there are currently no established effective treatments. Hence, the MAR assumption is considered a 
plausible missingness mechanism for the primary estimand in the case of neridronic acid.
6.3.2
Subject disposition 
Individual sites will be pooled by geographic region. Geographic regions are defined as 
USA/Canada, Europe, and Other Regions (including Asia-Pacific and Australia/New Zealand). 
For describing the subject disposition, the following populations will be summarized, overall and by
region (with percentage denominator being the number of allocated subjects):
•
Subjects allocated.
•
Subjects treated and the reasons for not being treated.
•
Interim Analysis Set.
•
Treatment Period A completers, i.e., subjects who received the full dose of all 4 planned 
infusions.
6.3.3
Premature terminations
Discontinuations from the trial and from IMP will be presented for the Interim Analysis Set overall, 
and per site. Reasons for discontinuations from the trial or from IMP will be presented for:
•
Subjects discontinued from the trial.
•
Subjects discontinued from IMP in Treatment Period A.
Percentage denominator will be the number of subjects discontinuing in the respective group. 
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6.3.4
Subject demographics
Subject demographics are age (years), weight (kg), height (cm), sex, race, ethnicity and will be 
descriptively summarized.
6.3.5
Baseline characteristics
Not applicable.
6.3.6
Previous and concomitant medication
Not applicable.
6.3.7
Subject medical history
Complex regional pain syndrome history will be descriptively summarized.
Continuous parameters based on date of Visit 1 are:
•
Time since inciting or precipitating event (month) – if unknown presented as unknown.
•
Time since onset of CRPS symptoms (month).
•
Time since diagnosis of CRPS (month).
Categorical baseline characteristics are: 
•
CRPS type (Type I, Type II, Unknown).
•
CRPS etiology.
−
Inciting or precipitating event (Missing, Known, Unknown).
−
Fracture, Sprain, Surgery, Crush, Others.
•
CRPS location (Left Body Site, Right Body Site, Upper Extremity, Lower Extremity, more 
than 1 Limb affected).
Except for CRPS type and inciting or precipitating event, multiple answers are possible.
6.3.8
Drug exposure 
Exposure will be displayed as the number of subjects receiving 1, 2, 3 or 4 infusions. It will be 
descriptively summarized.
6.3.9
Analysis of efficacy
The primary efficacy variable is the change from baseline to Week 12 in the average pain intensity
score. The average pain intensity score is calculated as the weekly average of the pain intensities
recorded daily (in the evening) in the electronic diary with a 24-hour recall period.
The average pain intensity score for Week x is based on the respective 24 hour-average pain 
intensity scores recorded daily in the electronic diary during Week x, i.e., 7-day intervals starting 
Day 1 to Day 7 for Week 1, and Day 8 to Day 14 for Week 2, etc.
Baseline is calculated as the mean of the average pain intensity score recorded daily in the
electronic diary during the baseline phase (Day -7 to Day -1).
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For the average pain intensity score for Week x, all available values in Week x will be used, no
imputation will be done for missing scores. If no pain scores are available for a week, the weekly
mean for that patient and week will remain missing. E-Diary data beyond Day 84 will not be used
for the analysis. For subjects without baseline value or subjects without any weekly average pain 
intensity, weekly scores will be imputed with zero as change from baseline and the baseline value I 
imputation will be done as the average baseline value of the treatment arm.
The statistical analysis will be similar to the primary analysis planned for the individual trials. The 
primary estimand is the difference in means of the primary efficacy endpoint of 400 mg intravenous 
neridronic acid compared to placebo for all allocated and treated subjects. This treatment policy or 
de facto estimand measures the effect of neridronic acid regardless of adherence to treatment or 
protocol. The primary estimand will be estimated by the analysis of the primary efficacy endpoint 
for the Interim Analysis Set. 
The primary analysis will fit a Mixed Model Repeated Measurement (MMRM) to the change from 
baseline in the average pain intensity scores from Week 1 to Week 12 recorded once daily in the 
electronic diary, including the covariate baseline pain intensity score, and the factors geographic 
region, week, treatment, and treatment-by-week interaction as fixed effects, and subject as random 
effect. If only one geographic region is represented in the Interim Analysis Set, this factor will be 
omitted from the model. An unstructured covariance matrix will be used to model the covariance 
structure, degrees of freedom will be estimated using the Kenward-Roger approximation. The 
primary efficacy analysis will be performed using the contrast, i.e., the mixed model Wald test, of 
neridronic acid 400 mg versus placebo at Week 12 of the treatment, week and treatment-by-week 
interaction term of the mixed effects model described above. Model-based parameter estimates 
(least square means), standard errors, 95% confidence intervals, and p-values will be tabulated. This 
analysis will be performed using only the observed values without imputation of missing values.
The point estimate for the observed difference in the means of neridronic acid and placebo will be 
calculated as the difference between the respective least squares means. If this estimate is ≥-0.3 
points on the NRS, futility will be concluded and the recommendation will be to stop both trials.
If the default Newton-Raphson algorithm used by statistical analysis software (SAS) PROC 
MIXED fails to converge, the Fisher scoring algorithm up to iteration 2 will be used (via the 
SCORING=2 option of the PROC MIXED statement) to obtain the initial values of covariance 
parameters (Mallinckrodt et al. 2008). If this alternative also fails to converge, then in addition, the 
no-diagonal factor analytic structure (via the TYPE=FA0(T) option of the REPEATED statement, 
where T = 12 is the total number of weeks in the 12-week trial period) will be used, which 
effectively performs the Cholesky decomposition of the covariance matrix and is numerically more 
stable. The first algorithm that leads to convergence in this sequence of fallback measures will be 
the algorithm used for the primary analysis of the trial.
A descriptive summary of the weekly averages and the changes from baseline will be generated by 
treatment group. A graphical plot of the model-based estimates and the 95% confidence interval of 
the change from baseline of the average pain intensity scores over the 12-week trial period will be 
created. Both treatments will be presented in one plot by week.
6.3.10
Analysis of adverse events
Not applicable.
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6.3.11
Analysis of laboratory parameters
Not applicable. 
6.3.12
Analysis of vital signs
Not applicable.
6.3.13
Analysis of further safety parameters
Not applicable. 
7
STATISTICAL OUTPUT DOCUMENTATION
The statistical output documentation will contain the original SAS-output for all analyses described 
in this SAP. The output will be kept at the independent statistician’s secure location until the 
closure of the trials, upon which they will be transferred to the sponsor.
8
CODING
Not applicable. 
9
STATISTICAL SOFTWARE
All summary tables and statistical analyses are generated using SAS Version 9.4 or higher.
10
REFERENCES
Mallinckrodt CH, Lane PW, Schnell D, Peng Y, Mancuso JP. Recommendations for the primary 
analysis of continuous endpoints in longitudinal clinical trials. Drug Inf J 2008; 42 (4): 303-19.
11
APPENDIX
Not applicable. 
11.1
Reference ranges for laboratory parameters
Not applicable.
11.2
Sponsor defined ranges for laboratory parameters
Not applicable.
11.3
Table shells, figure shells, and listings
A separate document containing the shells (i.e., without real data) for the tables, listings and figures 
will be prepared in parallel to the SAP.
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