Conditions: Complex Regional Pain Syndrome
Keywords: Neridronic Acid Neridronate CRPS RSD (reflex sympathetic dystrophy)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 580
Healthy volunteers: no

Brief summary:
The aim of this trial was to investigate the safety of intravenous neridronic acid in patients with complex regional pain syndrome (CRPS).

The trial was divided into 3 periods: a 60-day enrollment period, a treatment period consisting of 4 infusions over 10 days, and a follow-up period of approximately 50 weeks (with visits at Week 2, Week 6, Week 12, Week 26, Week 39, and Week 52).

Detailed description:
At the Enrollment Visit the trial objectives, procedures, and risks were explained to the participants and the informed consent form was signed. Medical history was obtained, a physical examination was conducted, and other safety assessments were performed. Signs and symptoms of CRPS were assessed to confirm the diagnosis of CRPS according to the Budapest clinical criteria. Participants were trained to report their pain. Calcium and vitamin D supplementation were initiated to ensure sufficient vitamin D levels prior to treatment.

Participants meeting all eligibility criteria received infusions of investigational medicinal product (IMP) during visits on Day 1, Day 4, Day 7, and Day 10. Flexibility of ±1 day was allowed for Day 4, Day 7, and Day 10 whilst ensuring a minimum period of 48 hours between infusions. During the treatment period and follow-up period, pain intensity ratings were captured at the site visits in a patient reported-outcome system.

Arms:
arm 1: Neridronic acid 100 mg administered on Day 1, Day 4, Day 7, and Day 10, resulting in a total dose of neridronic acid 400 mg.

Interventions: intervention 1: Neridronic acid
Intervention descriptions: intervention 1: Neridronic acid administered as intravenous infusion.

Protocol document:
Prot_000.pdf: 
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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:
KF7013-03
Title of trial:
Open-label safety trial of intravenous neridronic acid in subjects with 
complex regional pain syndrome (CRPS)
Brief title:
Safety of intravenous neridronic acid in CRPS
Indication:
Treatment of CRPS
International 
coordinating 
investigator: a
 MD
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Klinik und Poliklinik für Neurologie
Langenbeckstrasse 1, 55131 Mainz, Germany
Telephone: +49 (0) 613-117-
Trial sites:
Multi-site trial (approximately 70 sites in the United States and 
European Union)
Documentation of the involved trial sites will be maintained.
Trial sponsor:
Grünenthal GmbH, 52099 Aachen, Germany
Sponsor’s medically 
qualified person / 
Sponsor’s signatory: a
 MD, International Clinical Lead
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:
19 Jul 2016
1.0
All countries
Amendment 01:
21 Oct 2016
2.0
All countries
Amendment 02
20 Mar 2017
3.0
Germany
Amendment 03
19 Apr 2017
4.0
All countries
Amendment 04
17 Nov 2017
5.0
USA
IND number:
115811 (US sites only)
EudraCT number:
2016-001164-11
Universal Trial 
Number:
U1111-1180-8099
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1
PROTOCOL SYNOPSIS
1.1
Trial design
This is a multi-site, open-label, single-arm, Phase III safety trial of intravenous neridronic acid in 
subjects with CRPS.
1.1.1
Flow diagram summary of the trial
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, a treatment period consisting of 
4 infusions over 10 days, and a follow-up period of approximately 50 weeks (Visit 6 [Week 2] 
through Visit 11 [Week 52]). The subjects are expected to be in the trial for approximately 
60 weeks (14 months). See Section 1.1.1 for a summary of the trial as a flow diagram and 
Section 1.6 for a tabular schedule of events.
1.2
Trial objectives, endpoints, and outcomes
Objective
Endpoint/Outcome
Primary
Primary
To assess the safety and tolerability of 
neridronic acid in subjects with CRPS.
•
Occurrence of any treatment emergent adverse event (TEAE).
Secondary
Secondary
To assess the safety and tolerability of 
neridronic acid in subjects with CRPS.
•
Occurrence of permanent discontinuation from treatment due to 
an adverse event.
To assess the efficacy of neridronic acid in 
treatment of CRPS.
•
Change from baseline to Week 12 and Week 26 in the current 
pain intensity score, using a numerical rating scale (NRS).
•
Response to treatment, defined as at least 30% and at least 50% 
decrease from baseline in the current pain intensity score, at 
Week 12 and Week 26.
•
Patient Global Impression of Change (PGIC) at Week 12 and 
Week 26.
•
Change from baseline to Week 12 and Week 26 in the Pain 
Interference score of the Brief Pain Inventory (BPI).
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Enrollment Period
Treatment Period
Visit 4
Visit 5
Visit 1  
Visit 2
Visit 3
Day 1
Day 4
Day 7
Day 10
Neridronic acid 100 mg will be administered
on Day 1. Day 4. Day 7. and Day 10
Follow-up Period
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Week 2
Week 6
Week 12
Week 26
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Other data to be collected that is not directly attributed to or considered as an endpoint
To assess the safety and tolerability of neridronic acid in subjects with CRPS.
•
Occurrence of permanent discontinuation from treatment due to deterioration in renal function.
To assess the bone safety of neridronic acid in subjects with CRPS
•
Occurrence of signs of osteomalacia, based on histology and quantitative bone histomorphometry, in 
subjects undergoing bone biopsy.
To assess the efficacy of neridronic acid in treatment of CRPS
•
Change from baseline to Week 12 and Week 26 in the worst pain intensity score, using a NRS.
•
Change from baseline to Week 12 and Week 26 in the average pain intensity score, using a NRS.
•
Change from baseline to Week 12 and Week 26 in the Pain Disability Index (PDI) score.
•
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 12 and Week 26 in the Pain Anxiety Symptom Scale (PASS) score.
•
Change from baseline to Week 12 and Week 26 in the Center for Epidemiological Studies Depression 
Scale (CES-D) score.
•
Change from baseline to Week 12 and Week 26 in the CRPS Severity Score.
To assess the pharmacodynamics of neridronic acid in subjects with CRPS
•
Change from baseline to Week 12 and Week 26 in concentrations of bone turnover markers (C-terminal 
telopeptide of type I collagen [CTX], bone alkaline phosphatase [BAP], and procollagen type I amino-
terminal propeptide [PINP]) in serum.
•
Change from baseline to Week 26 in bone mineral density (BMD) in the lumbar spine in subjects 
undergoing dual-energy X-ray absorptiometry (DXA; US sites only).
•
Change from baseline to Week 26 in BMD in regions of interest (ROIs) of the CRPS-affected limb, relative 
to the contralateral limb, in subjects undergoing DXA (US sites only).
•
Change from baseline to Week 26 in volume of bone marrow lesions in ROIs of the CRPS-affected limb, 
relative to the contralateral limb, in subjects undergoing magnetic resonance imaging (MRI; US sites only).
Collection of health economics outcome and work productivity data (US sites only)
•
Work Productivity and Activity Impairment Questionnaire: CRPS (WPAI: CRPS) assessment on Day 1, at 
Week 26, and at Week 52.
•
Medical resources utilization and health economics data collection on Day 1, at Week 26, and at Week 52.
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1.3
Trial subjects – the population to be studied
1.3.1
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.
4.
Ongoing moderate to severe chronic pain, including a baseline current pain intensity score of 
4 using an 11-point NRS, referring to the CRPS-affected limb, at Visit 2 (prior to dosing).
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 trials of at least 2 treatments for CRPS, one of 
which must be a pharmacologic treatment (see Section 1.4.3).
6.
Women of child-bearing potential must have a negative urine beta-human chorionic 
gonadotropin (β-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 <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 impairment).
1.3.2
Exclusion criteria
1.
Evidence of renal impairment (estimated glomerular filtration rate [eGFR] <60 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 creatinine ratio [ACR] >150 mg/g), based on 
central safety laboratory data obtained prior to Visit 2, or a history of chronic kidney disease. 
Note: a single repeat laboratory test is allowed.
2.
Serum calcium or magnesium values 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); a history of hypocalcemia or a metabolic disorder anticipated to increase risk for 
hypocalcemia (e.g., hypoparathyroidism); concomitant use of drug(s) with known potential to 
cause hypocalcemia (e.g., aminoglycosides).
3.
Vitamin D deficiency, defined as a 25(OH)D level <30 ng/mL, 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 must be documented prior to allocation to 
investigational medicinal product (IMP).
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4.
Corrected QT interval (according to Fridericia’s formula; QTcF) >470 ms (average of 
3 electrocardiograms [ECGs] obtained at Visit 1); serum potassium outside the central 
laboratory’s reference range at Visit 1; 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 
other known risk factor for torsade de pointes.
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, escotalopram) or tricyclic antidepressants 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 until at least 4 days after the last 
infusion of IMP.
6.
Anticipated requirement for treatment with oral or intravenous bisphosphonate for another 
condition such as osteoporosis during the trial, or administration of denosumab (Prolia®) or 
other drugs affecting bone turnover or bone metabolism 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 predispose 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 2.
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 >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, 3 days apart, are 2-fold upper limit of normal.
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17. Participation in another investigational drug trial within 3 months prior to Visit 1 or any 
previous trial with neridronic acid, with the exception of subjects participating in KF7013-01 
who were assigned to placebo and did not receive 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 1.4.3).
20. Subjects incapable of signing the informed consent.
1.4
Trial treatments
1.4.1
Investigational medicinal products
The first batch of IMP will be provided to sites in the US in glass ampules, each containing 108 mg 
sodium neridronate hemi hydrate (equivalent to 100 mg neridronic acid) in a total volume of 8 mL. 
Subsequent batches of IMP will be supplied in vials.
Sites in the EU will receive all batches of IMP in glass vials.
The full contents of a single ampule or 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.
1.4.2
Other medication
Tetracycline hydrochloride 250 mg capsules for oral administration (applicable only for the subset 
of subjects at US sites undergoing the bone biopsy).
1.4.3
Prior/concomitant medications or therapies
Enrolled subjects must have failed trials of at least 2 treatments for CRPS, 1 of which must be a 
pharmacologic treatment. A failed trial is defined by continuing pain. Such treatments may be prior 
to or continuing at enrollment and can include any analgesic medication (including non-steroidal 
anti-inflammatory drugs [NSAIDs], opioids, antidepressants, etc.), interventional therapy (e.g., 
nerve block or spinal cord stimulation), or physical therapy.
Subjects are encouraged to continue standard of care interdisciplinary treatment for CRPS, 
including follow-up for physical therapy, occupational therapy, cognitive behavioral therapy, and 
graded motor imagery (including mirror feedback).
Subjects may continue treatment with allowed concomitant medications and therapies, including 
opioids and other analgesics, if they are on a stable, well-defined treatment regimen for at least 
1 month prior to treatment and are anticipated to be able to maintain the treatment regimen, in the 
opinion of the investigator. Stable 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. Changes to 
concomitant medications and therapies (e.g., use of short acting opioids for CRPS flares) may be 
allowed during the course of the trial and must be discussed with the medical monitor and 
documented in the case report form (CRF).
Sites will provide subjects with supplemental calcium and vitamin D, starting from Visit 1 and 
continuing through to the end of the trial. Acetaminophen (paracetamol) is recommended for 
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prophylaxis and treatment of flu-like symptoms that are commonly associated with the first 
intravenous administration of bisphosphonates (see Section 8.2 for details).
The following are forbidden as concomitant medications and therapies during the trial:
•
Drugs with the potential to cause hypocalcemia (e.g., aminoglycosides). Subjects on a 
stable dose of furosemide or other loop diuretics may receive treatment with IMP as long as 
no dosage changes in the diuretic medications are anticipated and calcium levels are in the 
reference ranges.
•
Oral or intravenous bisphosphonates, calcitonin, denosumab, or other bone-active drugs 
(e.g., teriparatide).
•
High-dose opioid analgesics (>200 mg morphine equivalent daily dose) or combinations of 
opioids and benzodiazepines or any other treatment regimen 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).
•
Nerve blocks, radiofrequency ablation or other sympathectomy procedures, hyperbaric 
oxygen treatments, ketamine infusions, intravenous immunoglobulin, or other experimental 
therapies.
•
Investigational drugs.
The following medications and therapies are forbidden from 7 days prior to allocation until 4 days 
after the last infusion:
•
Drugs with a known risk of torsades de pointes, excluding selective serotonin re-uptake 
inhibitor antidepressants (e.g., citalopram, escitalopram) and tricyclic antidepressants if QT 
interval values met entry criteria, subjects were on a stable dose for at least 1 month prior to 
allocation, and doses are expected to stay stable throughout the trial.
1.5
Statistical analyses
As this is a single-arm trial, no treatment comparisons will be conducted, but development from 
baseline over time will be investigated. All analyses in this trial will be of exploratory nature. No 
statistical testing of inference is planned in this trial. There will be no multiplicity adjustment for 
any of the analyses. All confidence intervals used to describe the data will be determined using a 
95% confidence level.
1.5.1
Sample size rationale
The sample size is intended to maximize available safety data in line with the FDA regulatory 
requirements to support product registration. It is estimated that approximately 290 subjects will be 
included in this trial.
If the expected number of bone biopsies or bone densitometry and MRI assessments are not 
obtained, it is not planned to increase the number of subjects included in the trial.
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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. The Safety Set will be the primary analysis set in this trial.
Full Analysis Set:
All subjects who are allocated and treated. In this trial the Full 
Analysis Set coincides with the Safety Set.
Treatment Completers 
Set:
All treated subjects who completed IMP administration according to 
the protocol, i.e., subjects who received the full dose of all 4 planned 
infusions of IMP.
Pharmacodynamic Set:
All treated subjects with at least 1 non-missing value for at least 1 of 
the bone turnover markers.
Bone Biopsy Set:
All subjects with at least 1 bone biopsy evaluable for histology or 
histomorphometry.
Bone Imaging Set:
All subjects with at least 1 DXA or MRI image evaluable for BMD
(DXA) or bone marrow lesion volume (MRI).
1.5.3
Statistical methods and analysis
Subject disposition will be summarized descriptively for all enrolled subjects. Discontinuations will 
be summarized descriptively for all allocated subjects. Demographic data, baseline characteristics, 
medical history, concomitant medications, and exposure will be summarized descriptively for the 
Safety Set. Pharmacodynamic parameters will be summarized descriptively for the 
Pharmacodynamic Set.
Primary safety endpoint
The primary endpoint of this trial is a binary endpoint assessing whether or not a subject 
experienced any TEAE. The primary safety endpoint will be analyzed in the SAF.
Secondary safety endpoints and other safety data
The incidences and incidence rates of all adverse events will be summarized descriptively.
Permanent discontinuations from treatment due to adverse events will be summarized descriptively. 
The distribution of time to onset of any TEAE will be summarized using time-to event methods. A 
graphical display using Kaplan-Meier methods displaying subjects at risk per time point will also be 
produced.
Safety laboratory values (hematology, clinical chemistry, and urinalysis), vital signs (systolic and 
diastolic blood pressure, pulse rate, respiratory rate, body weight, and body mass index), 12-lead 
ECG, and further safety parameters will be summarized descriptively.
All safety analyses will be conducted on the Safety Set.
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Secondary efficacy endpoints and other efficacy data
The analysis of all secondary efficacy endpoints and other efficacy data will be exploratory and will 
be summarized using descriptive statistics unless stated otherwise. Analyses will be performed on 
all post baseline measurements.
All efficacy analyses will be conducted on the Full Analysis Set.
Handling of missing data
Missing data will not be imputed in this trial. The number of missing data will be included in all 
descriptive summaries.
A mixed-effects model for repeated measurements (MMRM) will be conducted on the observed 
values of the change in current pain intensity score. An MMRM leads to unbiased estimates if the 
missingness mechanism is missing-at-random. Due to the long-acting effect of neridronic acid, 
missing-at-random is considered a clinically plausible assumption. The MMRM in this trial will 
include pooled site, baseline pain intensity and week as fixed effects and subject as a random effect. 
An unstructured covariance matrix will be used to model the covariance structure. Least squares 
means, standard errors, and 95% confidence intervals for the change from baseline will be obtained.
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1.6
Schedule of events
Enrollment 
Period
Treatment Period
Follow-up Period
Trial procedure
Visit 1 a
Visit 2
Visit 3 b
Visit 4 b Visit 5 b
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Day -60
to Day -1
Day 1
Day 4
(±1 day)
Day 7
(±1 day)
Day 10
(±1 day)
Week 2
(±2 days)
Week 6
(±7 days)
Week 12
(±7 days)
Week 26
(±15 days)
Week 39
(±15 days)
Week 52
(±15 days)
Obtain written informed consent
X
Record demographic data
X
Record medical history d
X
Record dental history e
X
Dispense calcium and vitamin D 
supplements f
X
Record prior medications and 
therapies
X
Review inclusion/exclusion 
criteria g
X 
X 
Check subject discontinuation 
criteria
X
X
X
X
X
X
X
X
X
Check IMP suspension criteria i
X
X
X
X
Record physical examination 
outcome k
X
X
X
X
X
X
Record vital signs l
X
X
X
X
X
X
X
X
X
X
X
Record 12-lead ECG m
X
X 
X 
X 
X 
X
X
X
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Enrollment 
Period
Treatment Period
Follow-up Period
Trial procedure
Visit 1 a
Visit 2
Visit 3 b
Visit 4 b Visit 5 b
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Day -60
to Day -1
Day 1
Day 4
(±1 day)
Day 7
(±1 day)
Day 10
(±1 day)
Week 2
(±2 days)
Week 6
(±7 days)
Week 12
(±7 days)
Week 26
(±15 days)
Week 39
(±15 days)
Week 52
(±15 days)
Perform continuous real-time ECG 
monitoring
X
X
X
X
Record concomitant medications 
and therapies
X
X
X
X
X
X
X
X
X
X
X
Ask the subject to complete pain 
intensity assessments 
X
X
X
X
X
X
X
X
X
X
X
Ask the subject to complete the 
PGIC
X
X
X
X
X
Ask the subject to complete the BPI 
interference scale
X
X
X
X
X
X
Ask the subject to complete the PDI 
X
X
X
X
X
X
Ask the subject to complete the
EQ-5D-5L
X
X
X
X
X
X
Ask the subject to complete the 
PASS
X
X
X
X
X
X
Ask the subject to complete the 
CES-D
X
X
X
X
X
X
Ask the subject to complete the 
WPAI: CRPS w
X
X
X
Collect medical resources 
utilization and health economics 
data w
X
X
X
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Enrollment 
Period
Treatment Period
Follow-up Period
Trial procedure
Visit 1 a
Visit 2
Visit 3 b
Visit 4 b Visit 5 b
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Day -60
to Day -1
Day 1
Day 4
(±1 day)
Day 7
(±1 day)
Day 10
(±1 day)
Week 2
(±2 days)
Week 6
(±7 days)
Week 12
(±7 days)
Week 26
(±15 days)
Week 39
(±15 days)
Week 52
(±15 days)
Complete the assessment of the 
signs and symptoms of CRPS
o
X
X
X
X
X
X
X
Take blood for safety laboratory
X
X
X
X
X
X
X
X
X
X
X
Collect urine for urinalysis p
X
X
X
X
X
X
X
X
X
X
X
Take blood (in the morning) for 
bone turnover marker evaluation r
X
X
X
X
X
X
X
Perform a urine ß-HCG pregnancy 
test s
X
X
X
X
X
X
X
Perform urine drugs of abuse 
testing
X
Provide subject trial card
X
Collect subject trial card t
X
X
Perform bone imaging u, w
X
X
Perform bone biopsy v, w
X
Prescribe tetracycline x
X
Tetracycline dosing diary for 
recording tetracycline intake x
dispense
collect
Record adverse events n 
X
X
X
X
X
X
X
X
X
X
X
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Enrollment 
Period
Treatment Period
Follow-up Period
Trial procedure
Visit 1 a
Visit 2
Visit 3 b
Visit 4 b Visit 5 b
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Day -60
to Day -1
Day 1
Day 4
(±1 day)
Day 7
(±1 day)
Day 10
(±1 day)
Week 2
(±2 days)
Week 6
(±7 days)
Week 12
(±7 days)
Week 26
(±15 days)
Week 39
(±15 days)
Week 52
(±15 days)
Allocate to IMP h
X
Administer IMP j
X
X
X
X
All visits, except Visit 1, should be attended in a fasting state (at least 8 hours).
a) Baseline imaging assessments must be scheduled during the enrollment period for subjects undergoing DXA and MRI. Additional visits are allowed during the enrollment 
period to confirm normalization of safety laboratory values (e.g., for subjects with vitamin D deficiency). 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.
b) The target dosing schedule is Day 1, Day 4, Day 7, and Day 10. Flexibility of ±1 day is allowed for Day 4, Day 7, and Day 10, keeping the overall duration of the infusions 
within the 10-day period (11 days if Day 10 +1 day). A minimum period of 48 hours is required between infusions. In situations where treatment is temporarily discontinued 
(e.g., due to a potential safety concern or scheduling issue), and a decision is made (in consultation with the sponsor or sponsor’s designee) to resume treatment, the treatment 
period can be extended up to 21 days (i.e., Visit 5 should occur no later than 21 days after Visit 2).
d) Includes history of CRPS (date, location and type of precipitating event; date of onset of symptoms; date of diagnosis; specific location of signs and symptoms; and specific 
body site where diagnostic criteria are applied).
e) Dental history will include: date of last dental visit; dental extractions and other invasive dental surgery in 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 predispose to risk of medication-related osteonecrosis of the jaw.
f) 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.
g) Compliance with inclusion and exclusion criteria must be confirmed before allocation to IMP, including pain score of at least 4 on the NRS.
h) Allocation must be performed using the interactive response technology system.
i) Subjects must be assessed prior to each infusion. This includes assessment for signs and symptoms of ocular inflammation, signs of proteinuria (see footnote p), and signs of 
dehydration. Subjects must be well hydrated prior to the start of infusions. Central safety laboratory data from the previous visit, in particular eGFR, must be evaluated prior to 
each infusion.
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j) All baseline measurements (including blood sampling for hematology and clinical chemistry, urinalysis, ECG, vital signs, and physical examination) must be completed and 
results available 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]).
k) After Visit 1, record any changes from the previous visit.
l) At Visit 2 through Visit 5, vital signs will be taken once at least 15 minutes before the infusion and once at least 15 minutes after the infusion. Body weight will be included as 
a vital sign and will be measured at all visits (only once at Visit 2 to Visit 5, prior to the infusion).
m) At Visit 2 through Visit 5, triplicate ECGs will be recorded once at least 15 minutes before the infusion and once at least 15 minutes after the infusion. A triplicate ECG will 
be recorded for all other visits.
n) Subjects should be queried for any events occurring since the previous visit; any events noted at Visit 1 should be documented as medical history or as part of physical 
examination results.
o) The diagnosis of CRPS must be confirmed using the tablet computer at Visit 1 according to the clinical diagnostic criteria recommended by the IASP (Budapest clinical 
criteria) (Section 12.2.3.1). The number of signs and symptoms of CRPS at Visit 2, and Visit 7 to Visit 11, inclusive, will be summed for determination of the CRPS Severity 
Score (Section 12.4.8).
p) At Visit 2 through Visit 5, urine collection must be performed prior to infusion. In addition to the sample for central safety laboratory analysis, a local dipstick evaluation for 
determination of urinary albumin creatinine ratio must be performed prior to the start of infusion.
r) C-terminal telopeptide of type I collagen (CTX), bone alkaline phosphatase (BAP), and PINP (procollagen type I amino-terminal propeptide).
s) For women of child-bearing potential, a negative urine pregnancy test result must be obtained prior to each infusion. For subjects who discontinue the trial prior to completion, 
pregnancy testing should be performed at the Early Termination Visit (whose procedures are identical to Visit 11).
t) The subject card is to be returned at the final visit or at the Early Termination Visit in the case of early discontinuation from the trial.
u) It is planned to perform bone densitometry (DXA) and MRI in a subset of 30 subjects.
v) A single bone biopsy will be obtained from the iliac crest, following tetracycline double-labeling, in a subset of subjects. The biopsy should be scheduled to be performed 
26 weeks after the first administration of IMP. It is planned to obtain approximately 15 evaluable bone biopsy samples from approximately 20 subjects.
w) At US sites only.
x) For US subjects undergoing bone biopsy only.
ß-HCG = beta-human chorionic gonadotropin, BPI = Brief Pain Inventory, CES-D = Center for Epidemiological Studies Depression Scale, CRPS = complex regional pain 
syndrome, DXA = dual-energy X-ray absorptiometry, ECG = electrocardiogram, eGFR = estimated glomerular filtration rate, EQ-5D-5L = EuroQol-5 dimension 5 level, 
IASP = International Association for the Study of Pain, IMP = investigational medicinal product, MRI = magnetic resonance imaging, NRS = numerical rating scale, 
PASS = Pain Anxiety Symptom Scale, PDI = Pain Disability Index, PGIC = Patient Global Impression of Change, WPAI = Work Productivity and Activity Impairment 
Questionnaire.
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1.7
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
2
1.2
Trial objectives, endpoints, and outcomes
2
1.3
Trial subjects – the population to be studied
4
1.3.1
Inclusion criteria
4
1.3.2
Exclusion criteria
4
1.4
Trial treatments
6
1.4.1
Investigational medicinal products
6
1.4.2
Other medication
6
1.4.3
Prior/concomitant medications or therapies
6
1.5
Statistical analyses
7
1.5.1
Sample size rationale
7
1.5.2
Subject populations
8
1.5.3
Statistical methods and analysis
8
1.6
Schedule of events
10
1.7
References
15
2
TABLE OF CONTENTS
16
LIST OF IN-TEXT TABLES
20
3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
21
3.1
Abbreviations
21
3.2
Definition of terms
22
4
ETHICS
23
4.1
Independent ethics committees or institutional review boards
23
4.2
Subject information and informed consent
23
4.3
Informing the subject’s healthcare provider
24
5
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
24
5.1
Investigators and trial site personnel
24
5.1.1
Investigators
24
5.1.2
Trial site personnel assigned trial-related duties
24
5.2
Contract research organizations
25
5.3
The sponsor and sponsor’s personnel
25
5.4
Data monitoring committee
25
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6
INTRODUCTION AND TRIAL BACKGROUND
26
6.1
Introduction
26
6.2
Background to the IMP
26
6.3
Relevant non-clinical and clinical data
26
6.4
Trial rationale
27
7
TRIAL OBJECTIVES AND ENDPOINTS
27
8
TRIAL DESIGN
27
8.1
Discussion of the trial design
27
8.1.1
Rationale for the investigational medicinal product and the selected dose
28
8.1.2
Rationale for the number and the frequency of visits/assessments
28
8.2
Benefit/risk analysis
29
9
SUBJECT ENROLLMENT AND TRIAL DISCONTINUATION
34
9.1
Subject enrollment procedure
34
9.2
Inclusion/exclusion criteria
34
9.3
Subject discontinuation from the trial or IMP
34
9.3.1
Subject discontinuation from the trial
34
9.3.2
Subject discontinuation from the IMP
35
9.3.3
Procedure for the handling of discontinued subjects
37
9.3.4
Premature termination or suspension of the trial
38
10
TRIAL TREATMENTS
38
10.1
Investigational medicinal product
38
10.1.1
Identity and composition – neridronic acid
38
10.1.2
Preparation
39
10.1.3
Packaging and labeling
39
10.1.4
Delivery, storage, and disposal
39
10.2
Administration of investigational medicinal product
39
10.3
Method of assigning subjects to treatment (allocation)
40
10.4
Blinding and unblinding
40
10.5
Other medication
40
10.6
Allowed and forbidden prior/concomitant medications or therapies
40
10.7
Documentation of drug accountability
41
11
COURSE OF THE TRIAL AND CONDITIONS
41
11.1
Course of the trial
41
11.1.1
Enrollment period
41
11.1.2
Treatment period
42
11.1.3
Follow-up period
45
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11.2
Examination hierarchy and time windows
48
11.3
Conditions during the trial
48
11.3.1
Medical care
48
11.3.2
Meals and fluid intake restrictions
49
11.3.3
Dental hygiene
49
11.3.4
Counseling of women of reproductive age
49
11.4
Subject trial cards
49
11.5
Provisions of any additional care of subject after trial termination
50
12
TRIAL ASSESSMENTS
50
12.1
Overview of blood sampling in this trial
50
12.2
Collection of demographic data and other baseline characteristics
50
12.2.1
Demographic data
50
12.2.2
Prior and concomitant medication or therapies
50
12.2.3
Relevant prior/concomitant disease or surgical interventions
51
12.2.4
Other baseline characteristics
53
12.3
Collection of safety data
53
12.3.1
Adverse events
53
12.3.2
Vital signs
58
12.3.3
Twelve-lead electrocardiogram
59
12.3.4
Continuous real-time ECG monitoring
59
12.3.5
Safety laboratory
59
12.3.6
Physical examination
62
12.3.7
Urine beta-human chorionic gonadotropin pregnancy test
62
12.3.8
Bone biopsy procedures
62
12.4
Collection of efficacy data
63
12.4.1
Pain intensity
63
12.4.2
Patient Global Impression of Change
64
12.4.3
Brief Pain Inventory interference scale
64
12.4.4
Pain Disability Index
64
12.4.5
EuroQoL-5 dimension 5 level
65
12.4.6
Pain Anxiety Symptom Scale
65
12.4.7
Center for Epidemiological Studies Depression Scale
65
12.4.8
CRPS Severity Score
65
12.5
Collection of pharmacodynamic data
66
12.5.1
Bone turnover markers
66
12.5.2
Bone densitometry and magnetic resonance imaging
66
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12.6
Collection of health economics outcome and work productivity data (US 
sites only)
67
12.6.1
Work Productivity and Activity Impairment Questionnaire: CRPS
67
12.6.2
Medical resources utilization and health economics data collection
67
12.7
Appropriateness of measurements
67
12.8
Compliance
70
13
DOCUMENTATION OF TRIAL DATA
70
13.1
Case report forms
70
13.1.1
Subject tetracycline dosing diary
71
13.2
Subject reported outcomes
71
13.3
External data
71
13.4
Data management
71
13.5
Source data
71
13.6
Investigator’s site file and the trial master file
72
14
QUANTITATIVE ANALYSES
73
14.1
Statistical methods and sample size determination
73
14.1.1
Sample size rationale
73
14.1.2
General description of statistical analyses
73
14.1.3
Analysis populations (analysis sets)
73
14.1.4
Subject disposition
73
14.1.5
Analysis of demographic data and other baseline characteristics
74
14.1.6
Analysis of safety data
74
14.1.7
Analysis of efficacy data
75
14.1.8
Analysis of pharmacodynamic data
75
14.1.9
Analysis of bone imaging data
75
14.1.10
Analysis of health economics outcome and work productivity data
75
14.1.11
Interim analysis
75
14.1.12
Ad hoc meta-analyses
75
15
QUALITY SYSTEM, AUDIT, AND INSPECTION
76
15.1
Quality system
76
15.2
Data quality assurance
76
15.3
Inspections
76
16
GENERAL CONDITIONS AND AGREEMENTS
76
16.1
Insurance
76
16.2
Legal regulations
77
16.3
Contracts
77
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16.4
Subject data and data protection
77
16.5
Public disclosure
77
16.6
Trial results reporting
78
16.7
Approval
78
16.7.1
Sponsor
78
16.7.2
Coordinating investigator
78
17
REFERENCES
78
18
APPENDIX
82
18.1
List of potentially important medical concepts – classified by System 
Organ Class
82
18.2
Algorithm for follow-up investigation of potential or suspected cases of 
drug-induced liver injury
85
18.3
Subject reported outcomes
85
18.3.1
Patient Global Impression of Change
86
18.3.2
Brief Pain Inventory interference scale
87
18.3.3
Pain Disability Index
88
18.3.4
EuroQol-5 dimension 5 level
89
18.3.5
Pain Anxiety Symptom Scale
92
18.3.6
Center for Epidemiological Studies Depression Scale
93
18.3.7
Work Productivity and Activity Impairment Questionnaire: CRPS
94
18.4
Signs and symptoms of CRPS
95
18.5
Health Economics Outcome Questionnaire (sample)
96
19
PROTOCOL AMENDMENTS
101
19.1
Protocol amendment 01
101
19.2
Protocol amendment 02
118
19.3
Protocol amendment 03
120
19.4
Protocol amendment 04
127
LIST OF IN-TEXT TABLES
Table 1:
Reasons for compulsory and optional discontinuation of subjects
35
Table 2:
Reasons for permanent and temporary discontinuation of subjects from 
IMP
36
Table 3:
Planned approximate blood sampling volumes collected from each 
subject
50
Table 4:
Complex regional pain syndrome clinical diagnostic criteria 
recommended by the IASP; “Budapest clinical criteria”
52
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3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
3.1
Abbreviations
Abbreviation
Explanation
ACR
Albumin creatinine ratio
β-HCG
Beta-human chorionic gonadotropin 
BAP
Bone alkaline phosphatase
BMD
Bone mineral density
BPI
Brief Pain Inventory
CES-D
Center for Epidemiological Studies Depression Scale
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRF
Case report form
CRO
Contract research organization
CRPS(-I)(-II)
Complex regional pain syndrome (Type I) (Type II)
CTX
C-terminal telopeptide of type I collagen
DMC
Data monitoring committee
DXA
Dual-energy X-ray absorptiometry
ECG
Electrocardiogram
EFPIA
European Federation of Pharmaceutical Industries and Associations
eGFR
Estimated glomerular filtration rate
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
IMMPACT
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
IMP
Investigational medicinal product
IRB
Institutional review board
IRT
Interactive response technology
MDMA
3,4-methylendioxy methamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effects model for repeated measurements
MRI
Magnetic resonance imaging
NRS
Numerical rating scale
NSAID
Non-steroidal anti-inflammatory drug
ONJ
Osteonecrosis of the jaw
PASS
Pain Anxiety Symptom Scale
PDI
Pain Disability Index
PGIC
Patient Global Impression of Change
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Abbreviation
Explanation
PINP
Procollagen type I amino-terminal propeptide
QTcB
QT interval (corrected according to Bazett’s formula)
QTcF
QT interval (corrected according to Fridericia’s formula)
ROIs
Regions of interest
SAE
Serious adverse event
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 allocated 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.
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 who 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.
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 an enrollment failure.
Treated subjects
Subjects with at least 1 administration of IMP.
Treatment completers
Treated subjects who completed IMP administration according to the protocol, i.e., 
subjects who received the full dose of all 4 planned infusions of IMP.
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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. 
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/or 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.
Separate informed consent will be required from subjects participating in the bone biopsy 
assessment. Participation in the bone biopsy assessments will not be mandatory for participation in 
the trial.
Separate informed consent will be required from subjects participating in the imaging (DXA and 
MRI) assessments. Participation in these imaging evaluations is not mandatory for trial 
participation.
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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 the time of 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.
Country-specific coordinating investigators will be defined who are responsible for the coordination 
of principal investigators at multiple trial sites in 1 country.
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.
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.
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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 (CROs; commercial, academic or other, e.g., central laboratory 
facilities, trial supply management provider, electronic patient reported outcome 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.
5.4
Data monitoring committee
An external, independent data monitoring committee (DMC) will periodically review safety 
information from the trial and monitor trial conduct and overall progress.
The DMC will have the ability to make recommendations to the sponsor that might impact the 
future conduct of the trial. Procedures for and management of the DMC will follow the sponsor’s 
standard operating procedures (SOPs) and will be documented in the DMC Charter. The DMC for 
this trial is anticipated to convene approximately every 6 months, depending on subject accrual in 
the trial.
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6
INTRODUCTION AND TRIAL BACKGROUND
6.1
Introduction
Complex regional pain syndrome is a chronic, severe and frequently 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). CRPS is characterized by disproportionate pain, 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 approved pharmacological treatments for CRPS in the US, 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 indicate 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 open-label trial with a total dose of neridronic acid 400 mg is designed to obtain 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.
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.
More than 500 subjects have received parenteral neridronic acid in Phase II and Phase III trials 
intended for registration of intravenous or intramuscular formulations for the treatment of 
osteogenesis imperfecta, Paget’s disease, osteoporosis, and CRPS-I. Doses administered in these 
trials ranged from 12.5 mg to 400 mg, with the 400 mg dose administered as either a single 
intravenous infusion of approximately 5 hours, or divided into four 2-hour infusions of 100 mg 
administered over 10 days. Based on results of these trials, neridronic acid appears safe and well 
tolerated up to a dose of 400 mg as a single or divided infusion. Drug-related adverse events 
following intravenous and intramuscular administration of neridronic acid consisted predominantly 
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of fever and flu-like symptoms (e.g., arthralgia, myalgia) following the first administration, as well 
as pain, bruising, and tenderness at the injection site for intramuscular injections. Mean decreases in 
calcium and phosphate were noted in serum chemistry assessments, although individual subject out-
of-range values and symptomatic hypocalcemia were rare. Based on these findings, the adverse 
event profile of neridronic acid is considered to be similar to that of other aminobisphosphonates. 
The safety of neridronic acid is supported by spontaneous adverse event reporting, 
pharmacovigilance, and information from published trials.
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, active range of motion, 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. These results suggest 
intravenous neridronic acid 400 mg is effective and safe for treatment of CRPS-I.
6.4
Trial rationale 
The aim of this trial is to investigate the safety of intravenous neridronic acid in patients with 
CRPS. The trial is intended as an integral part of the overall safety assessment of neridronic acid, to 
support submission to regulatory agencies for product registration.
7
TRIAL OBJECTIVES AND ENDPOINTS
The trial objectives and endpoints are given in Section 1.2.
8
TRIAL DESIGN
8.1
Discussion of the trial design
This is a multi-site, open-label, single-arm, Phase III trial. A single-arm trial, without a placebo or 
other comparator, maximizes the number of subjects exposed to neridronic acid and is intended to 
provide adequate safety data to support product registration. Although efficacy assessments are 
included for exploratory purposes, results of these evaluations must be interpreted with caution in 
the absence of a comparator arm.
A subset of subjects will undergo iliac crest bone biopsy to assess bone histology and 
histomorphometry indices following treatment with neridronic acid 400 mg. The effect of 
neridronic acid on bone quality and mineralization was evaluated in biopsies from 14 patients with 
Paget’s disease receiving neridronic acid 250 mg (50 mg/day for 5 days; McCloskey et al. 1987; 
Atkins et al. 1987). Normal bone mineralization and bone formation were observed in biopsies from 
regions of non-pagetic bone (iliac crest), and improved indices of bone turnover were observed in 
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regions of pagetic bone. It is planned to obtain approximately 15 evaluable bone biopsy specimens 
from approximately 20 subjects. It is anticipated that bone biopsy specimen evaluation will confirm 
normal bone mineralization in the iliac crest at approximately 6 months following treatment with 
neridronic acid 400 mg. A 6 month time point was selected for the biopsy in order to match the 
slow kinetics of bone matrix and mineral apposition in humans, with approximately 6 months 
required to complete a single remodeling cycle (Riggs and Parfitt 2005).
It is anticipated that a subset of 30 subjects will undergo bone densitometry and MRI to assess the 
effect of neridronic acid on BMD and bone marrow lesions in CRPS-affected limbs, relative to the 
contralateral, unaffected limb. The same subject will be allowed to participate in both bone biopsy 
and bone densitometry and MRI sub studies if they are willing. This exploratory investigation is 
anticipated to corroborate published descriptions of decreased BMD and other bone abnormalities 
in the affected limbs of subjects with CRPS (Gatti et al. 2016) and may provide a foundation for 
future investigation of the effect neridronic acid on bone pathology in CRPS.
Rationale for the trial population
The trial population will include subjects with both CRPS-I and CRPS Type II (CRPS-II). Subjects 
with CRPS-II are poorly represented in clinical trials. However, the distinctions between these two 
subtypes are not always clear (Oaklander and Horowitz 2015; Bruehl 2015). Inclusion of subjects 
with CRPS-II is not anticipated to affect the safety objectives of this trial.
8.1.1
Rationale for the investigational medicinal product and the selected dose
A placebo-controlled trial in 82 subjects with CRPS-I indicated that 400 mg of neridronic acid, 
administered as four 2-hour infusions of 100 mg in 10 days, is safe, well-tolerated and effective for 
treatment of pain and other symptoms of CRPS (Varenna et al. 2013).
A pilot trial of neridronic acid involving cumulative intravenous doses of 200 mg, 300 mg, and 
400 mg neridronic acid in patients with CRPS-I suggested that the 400 mg cumulative dose was 
optimally effective. As the 4 x 100 mg dose regimen 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 neridronic acid 100 mg to treat Paget’s disease of bone, 
osteogenesis imperfecta, and CRPS-I is 2 hours. To limit the maximum concentrations (Cmax) in this 
trial to levels similar to those obtained in the KF7013-01 trial, in which neridronic acid 62.5 mg was 
infused in 2 hours, the infusion time has been extended to 4 hours.
Alternative dosage forms or routes of administration for neridronic acid are limited to an 
intramuscular dosage form (25 mg per ampule, available in Italy), which would be impractical for 
administering a 400 mg total dose. An oral dosage form is not available and would have practical 
limitations due to the very low bioavailability of bisphosphonates (typically reported in the range of 
1%).
8.1.2
Rationale for the number and the frequency of visits/assessments
The number of visits and visit frequency are the same as those in the previous KF7013-01 trial and 
are considered sufficient to assure subject safety and meet study objectives. 
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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 
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 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. Changes in analgesic 
medications and other treatments for CRPS may be permitted during the follow-up period. This will 
help to ensure that subjects in the trial will not suffer from untreated pain. 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, muscle pain, 
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, starting from approximately 1 hour 
prior to the first infusion and then approximately every 6 hours for the 72-hour period after the first 
infusion. Commercially available products and dosages 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 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.
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 
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neridronic acid will be discontinued at first signs of ocular inflammation, followed by an 
ophthalmologic exam.
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 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. Recommended doses are 500 mg to 1000 mg per day 
elemental calcium and approximately 1000 IU/day vitamin D. A combination product of calcium 
and vitamin D may be used. Subjects with vitamin D levels below 30 ng/mL at enrollment 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. Vitamin D will be reduced to approximately 
1000 IU/day prior to the start of treatment at Visit 2. Repeat laboratory testing for vitamin D is 
permitted during the enrollment period (up to a maximum of 4 times in 60 days). Investigators 
should promote compliance by instructing the subject to take the supplements as prescribed and by 
stating that compliance is important for subject safety.
Vitamin D will be measured and reviewed at each visit. If levels of 25(OH)D fall below 30 ng/mL, 
supplementation of vitamin D should be increased, as appropriate.
Class effect risks of intravenous aminobisphosphonates that may be associated with 
neridronic acid
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, 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 moderate to severe renal 
impairment will be excluded (for details, see exclusion criterion 1). Taking into account that renal 
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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), neridronic acid 400 mg will 
be administered as 4 infusions of neridronic acid 100 mg administered over 240 minutes at Visit 2, 
Visit 3, Visit 4, and Visit 5.
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). 
Medication-related osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ) 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 ONJ 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 BMD and lowered risk of clinical fracture in children and adults with osteogenesis 
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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.
Monitoring of changes in serum and urinary calcium may be helpful to predict effects of neridronic 
acid on bone mineralization, since decreases in these parameters, in the context of a compensatory 
increase in parathyroid hormone, likely indicate ongoing accretion of calcium into bone 
(McCloskey et al. 1987).
Additional information relevant for the safety profile
Pregnancy and breastfeeding
There are no adequate and well-controlled trials of neridronic acid in pregnant or lactating women. 
Although there are no data to suggest a 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 period 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.
Risks related to bone biopsies
Bone biopsies are performed as a minor outpatient surgery and are safe and generally well-tolerated
(Kann et al. 2006, Hernandez et al. 2008). Risks include bleeding, hematoma, infection, superficial 
nerve injury, and pain. Most subjects experience soreness over the biopsy area for 4 days to 5 days. 
Subjects with increased risk of bleeding (e.g., hemostasis disorders, concomitant treatment with 
antithrombotic drugs) will be excluded from the bone biopsy assessments.
It is unknown whether a bone biopsy could trigger or worsen CRPS in patients. The limited trials in 
which bone biopsies were performed in patients with CRPS or similar painful conditions have not 
suggested that this procedure would be likely to cause severe complications or worsening of CRPS, 
even when performed in a CRPS-affected region. Since biopsies will be performed only in a region 
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free of CRPS-related signs and symptoms, this is likely to mitigate the risk of worsening of the 
condition.
Side effects from tetracycline are rare, but may include skin rashes, photosensitivity, nausea and 
diarrhea. Women of child-bearing potential using oral contraceptives will be excluded due to 
potential risk that tetracycline may diminish contraceptive efficacy. Subjects with known allergy to 
tetracyclines will also be excluded.
Risks related to bone densitometry and magnetic resonance imaging
Bone densitometry using DXA is safe and well tolerated; radiation doses are very low (<5 µSv), 
generally 10-fold lower than a chest x-ray and 20-fold lower than a standard dental x-ray procedure.
Risks of MRI are due to metallic implants or other ferromagnetic foreign bodies that may be 
displaced and accelerated toward the magnet, causing tissue damage. Tattoos and cosmetics may 
contain particles of iron oxide or other metals and may cause burns or local irritation during MRI 
procedures. Claustrophobic reactions can occur. Ionizing radiation is not involved.
The investigator will assess the appropriateness of the subject for inclusion in the imaging subset 
and discuss the risks with the subject during the consenting process.
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).
Glass particle contamination may occur when opening ampules, which has the potential to cause 
harm if injected into the body. Particles of glass or other materials can cause blockages of small 
vessels and cause damage to internal organs. To reduce the risk of injection of glass particles from 
broken ampules, sites will receive training information on safe handling of glass ampules. The IMP 
will be withdrawn from ampules using a filter needle, which should prevent injection of any glass 
particles.
Blood sampling may cause pain or bruise at the site where the blood is taken due to insertion of the 
needle. Apart from the bone biopsies from a subset of subjects, 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 Food and Drug Administration (FDA) approved 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 safety as well as efficacy 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 CRPS 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, while 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
9.3.2
Subject discontinuation from the IMP
Discontinuation of IMP applies only to the treatment period. Subjects who are discontinued from 
IMP should not be discontinued from the trial except for the 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 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, the treatment period may be extended to a 
maximum of 21 days (i.e., Visit 5 should occur no later than 21 days after Visit 2). Visit 6 will be 
scheduled to occur 4 days (±2 days) after Visit 5, but all subsequent visits should occur as originally 
scheduled relative to Visit 2 (e.g., Visit 7 will be 42 days [6 weeks] after Visit 2). No more than 
4 infusions may be administered during the treatment period, and a minimum of 48 hours between 
any 2 infusions is required.
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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
Evidence suggestive of a possible change in renal function:
•
A persistent 25% decrease from baseline (last value observed prior to 
treatment) in the eGFR, based on repeated central laboratory results from 
blood samples obtained at least 1 week apart a.
X
•
A 25% decrease from baseline in the eGFR. If a repeated measurement of 
eGFR is within 75% or more of the baseline value, the subject may resume 
treatment a.
X
•
A persistent urinary ACR >300 mg/g based on quantitative urinary albumin 
and creatinine data from the central laboratory, with 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.
X
•
A persistent eGFR <50 mL/min/1.73 m2 and urinary ACR >150 mg/g 
based on repeated quantitative data from the central laboratory, with blood 
and urine samples obtained at least 1 week apart.
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
•
Resolution of signs and symptoms within 5 days.
X
•
Persistent or recurrent signs and symptoms.
X
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Discontinuation from IMP
Reason
Permanent
Temporary
At any point during the treatment period if further assessment may be helpful to 
assure safety of the subject.
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 prohibited 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) Baseline values of eGFR are obtained from central laboratory results after Visit 2 (based on the blood sample taken at 
Visit 2 prior to the first administration of IMP). Evaluation of change from baseline in eGFR must occur prior to Visit 4 
and Visit 5, based on assessment of central laboratory results from blood samples taken prior to Visit 3 and Visit 4, 
respectively.
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.
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 CRF.
•
Complete activities related to discharge of the subject 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 11. 
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 
who are permanently discontinued from IMP should proceed to Visit 6 at approximately 4 days 
after the last infusion, if possible; Visit 7 and subsequent visits will proceed according to the 
original visit schedule (relative to Visit 2).
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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, or 
in response to a recommendation by the independent DMC.
•
Decision by the sponsor to terminate the program or for other strategic reasons.
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.
10
TRIAL TREATMENTS
10.1
Investigational medicinal product
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.
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For further information about the identity and composition of IMP, see the clinical supply 
specification (available on request) and the current neridronic acid investigator’s brochure.
10.1.2
Preparation
The first batch of IMP will be provided to sites in the US in glass ampules and must be removed 
using a filter needle (to remove any possible glass particles). Instructions will be provided for 
proper handling of ampules and filter needles. Subsequent batches of IMP will be supplied in vials, 
which do not require the use of filter needles. Instructions will be provided for the proper handling 
of vials.
Sites in the EU will receive all batches of IMP in glass 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, United 
States Pharmacopeia (USP) grade saline for injection) to a volume of approximately 500 mL. 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 CRF.
10.1.3
Packaging and labeling
The IMP will be supplied in kits consisting of either 4 ampules (initially for US sites) or 4 vials (US 
and EU sites) of IMP. A single kit will be used for each trial subject (i.e., subjects will not receive a 
mixture of ampules and vials). Ampules or vials are labeled according to each infusion visit (Visit 2 
[Day 1], Visit 3 [Day 4], Visit 4 [Day 7], and Visit 5 [Day 10]).
Replacement kits will be available in the event of broken ampules/vials or mishandling during the 
transfer process that raises concerns for potential contamination.
For detailed information about the packaging and labeling, see the clinical supply specification 
(available on request).
10.1.4
Delivery, storage, and disposal
For detailed information about the distribution of the IMP, see the clinical distribution specification 
(available on request).
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 product
The full contents of a single ampule or 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, 
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Visit 3, Visit 4 and Visit 5, resulting in a total dose of neridronic acid 400 mg. The complete 
solution volume of 500 ± 50 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 CRF. No more than 4 infusions (400 mg total dose) may be administered to any subject in the 
trial.
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 
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 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)
Subjects will be assigned to an IMP kit in sequential order using an interactive response technology 
(IRT) system.
10.4
Blinding and unblinding
Not applicable as this is an open trial.
10.5
Other medication
Name:
Tetracycline hydrochloride.
Active component:
Tetracycline.
Dose (strength):
Tetracycline hydrochloride 250 mg capsules for oral administration.
Supplier:
Grünenthal GmbH, Aachen, Germany.
Tetracycline hydrochloride is applicable only for the subset of subjects at US sites undergoing the 
bone biopsy.
Further details regarding administration are provided in Section 12.3.8.
10.6
Allowed and forbidden prior/concomitant medications or therapies
Information on allowed or forbidden prior/concomitant medications or therapies is provided in 
Section 1.4.3.
Recommendations for supplementation of calcium and vitamin D and use of acetaminophen for 
alleviating symptoms of the acute phase reaction are provided in Section 8.2.
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For the purposes of data reporting by the site, the cut-off 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.
10.7
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 IMP. 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 IMP(s) 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 IMP(s), and the 
administration/intake as documented in the CRF, with clarification of any discrepancies or 
inconsistencies.
11
COURSE OF THE TRIAL AND CONDITIONS
See Section 1.1.1 for a flow diagram summary of the trial and Section 1.6 for a tabular schedule of 
events.
11.1
Course of the trial
All visits, except Visit 1, should be attended in a fasting state (at least 8 hours). A non-fasting state 
does not constitute a protocol deviation.
The site should remind the subject 2 days before the scheduled visits that they should come to the 
site in a fasted state.
11.1.1
Enrollment period
The general suitability of the subjects for the trial will be assessed during the enrollment period.
Baseline imaging assessments must be scheduled during the enrollment period for subjects who 
consent to participate in bone imaging assessments (DXA and MRI).
Additional visits are allowed during the enrollment period to confirm normalization of safety 
laboratory values (e.g., for subjects with vitamin D deficiency).
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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.
11.1.1.1
Visit 1 (Day -60 to Day -1)
The following evaluations will be performed:
•
Obtain written informed consent.
•
Record demographic data.
•
Record medical history (includes history of CRPS; for further details, see Section 1.6).
•
The diagnosis of CRPS must be confirmed using the tablet computer at Visit 1 according to 
the clinical diagnostic criteria recommended by the IASP (Budapest clinical criteria) (for 
further details, see Section 12.2.3.1).
•
Record dental history (for further details, see Section 1.6).
•
Dispense calcium and vitamin D supplements (for further details, see Section 1.6).
•
Record prior medications and therapies.
•
Review inclusion/exclusion criteria.
•
Record physical examination outcome.
•
Record vital signs.
•
Record triplicate 12-lead ECG.
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis.
•
Perform a urine ß-HCG pregnancy test (for women of child-bearing potential).
•
Perform urine drugs of abuse testing.
•
Provide subject trial card.
•
Perform bone imaging (DXA and MRI will be performed in a subset of approximately 
30 subjects [from US sites only]).
•
Record adverse events (any events noted should be documented as medical history or as 
part of physical examination results).
11.1.2
Treatment period
The target dosing schedule is Day 1, Day 4, Day 7, and Day 10. Flexibility of ±1 day is allowed for 
Day 4, Day 7, and Day 10, keeping the overall duration of the infusions within the 10-day period 
(11 days if Day 10 +1 day). A minimum period of 48 hours is required between infusions.
Central safety laboratory data from the previous visit, in particular eGFR, must be evaluated prior to 
each infusion.
See Section 9.3.2 for details of temporary suspension of IMP.
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Due to the number of procedures and assessments at the infusion visits, subjects should arrive at the 
site at least 1 hour to 2 hours prior to the start of the infusion; subjects will remain at the center for 
1 hour after the end of the infusion for evaluation.
11.1.2.1
Visit 2 (Day 1)
The following evaluations will be performed:
•
Review inclusion/exclusion criteria.
•
Check subject discontinuation criteria.
•
Check IMP suspension criteria (for further details, see Section 9.3.2).
•
Record physical examination outcome (changes from the previous visit).
•
Record vital signs (once at least 15 minutes before the infusion and once at least 15 minutes 
after the infusion).
•
Record triplicate 12-lead ECG (once at least 15 minutes before the infusion and once at 
least 15 minutes after the infusion).
•
Perform continuous real-time ECG monitoring (for details, see Section 12.3.4).
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Ask the subject to complete the BPI interference scale.
•
Ask the subject to complete the PDI.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PASS.
•
Ask the subject to complete the CES-D.
•
Ask the subject to complete the WPAI: CRPS (US sites only).
•
Collect medical resources utilization and health economics data (US sites only).
•
Complete the assessment of the signs and symptoms of CRPS.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis and local dipstick evaluation (calculate 
urinary ACR).
•
Take blood (in the morning) for bone turnover marker evaluation.
•
Perform a urine ß-HCG pregnancy test (for women of child-bearing potential).
•
Record adverse events (based on subject reporting before, during, and after infusion).
•
Allocate to IMP (using IRT system).
•
Administer IMP (for further details, see Section 10.2).
11.1.2.2
Visit 3 (Day 4; ±1 day)
The following evaluations will be performed:
•
Check subject discontinuation criteria.
•
Check IMP suspension criteria (for further details, see Section 9.3.2).
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•
Record vital signs (once at least 15 minutes before the infusion and once at least 15 minutes 
after the infusion).
•
Record triplicate 12-lead ECG (once at least 15 minutes before the infusion and once at 
least 15 minutes after the infusion).
•
Perform continuous real-time ECG monitoring (for details, see Section 12.3.4).
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis and local dipstick evaluation (calculate 
urinary ACR).
•
Perform a urine ß-HCG pregnancy test (for women of child-bearing potential).
•
Record adverse events.
•
Administer IMP (for further details, see Section 10.2).
11.1.2.3
Visit 4 (Day 7; ±1 day)
The following evaluations will be performed:
•
Check subject discontinuation criteria.
•
Check IMP suspension criteria (for further details, see Section 9.3.2).
•
Record vital signs (once at least 15 minutes before the infusion and once at least 15 minutes 
after the infusion).
•
Record triplicate 12-lead ECG (once at least 15 minutes before the infusion and once at 
least 15 minutes after the infusion).
•
Perform continuous real-time ECG monitoring (for details, see Section 12.3.4).
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis and local dipstick evaluation (calculate 
urinary ACR).
•
Perform a urine ß-HCG pregnancy test (for women of child-bearing potential).
•
Record adverse events.
•
Administer IMP (for further details, see Section 10.2).
11.1.2.4
Visit 5 (Day 10; ±1 day)
The following evaluations will be performed:
•
Check subject discontinuation criteria.
•
Check IMP suspension criteria (for further details, see Section 9.3.2).
•
Record vital signs (once at least 15 minutes before the infusion and once at least 15 minutes 
after the infusion).
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•
Record triplicate 12-lead ECG (once at least 15 minutes before the infusion and once at 
least 15 minutes after the infusion).
•
Perform continuous real-time ECG monitoring (for details, see Section 12.3.4).
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis and local dipstick evaluation (calculate 
urinary ACR).
•
Perform a urine ß-HCG pregnancy test (for women of child-bearing potential).
•
Record adverse events.
•
Administer IMP (for further details, see Section 10.2).
11.1.3
Follow-up period
11.1.3.1
Visit 6 (Week 2; ±2 days)
The following evaluations will be performed:
•
Check subject discontinuation criteria.
•
Record vital signs.
•
Record triplicate 12-lead ECG.
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis.
•
Take blood (in the morning) for bone turnover marker evaluation.
•
Record adverse events.
11.1.3.2
Visit 7 (Week 6; ±7 days)
The following evaluations will be performed:
•
Check subject discontinuation criteria.
•
Record vital signs.
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Ask the subject to complete the PGIC.
•
Ask the subject to complete the BPI interference scale.
•
Ask the subject to complete the PDI.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PASS.
•
Ask the subject to complete the CES-D.
•
Complete the assessment of the signs and symptoms of CRPS.
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•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis.
•
Take blood (in the morning) for bone turnover marker evaluation.
•
Record adverse events.
11.1.3.3
Visit 8 (Week 12; ±7 days)
The following evaluations will be performed:
•
Check subject discontinuation criteria.
•
Record physical examination outcome (changes from the previous visit).
•
Record vital signs.
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Ask the subject to complete the PGIC.
•
Ask the subject to complete the BPI interference scale.
•
Ask the subject to complete the PDI.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PASS.
•
Ask the subject to complete the CES-D.
•
Complete the assessment of the signs and symptoms of CRPS.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis.
•
Take blood (in the morning) for bone turnover marker evaluation.
•
Record adverse events.
•
Prescribe tetracycline and dispense tetracycline dosing diary to US subjects undergoing a 
bone biopsy for recording the intake of tetracycline.
11.1.3.4
Visit 9 (Week 26; ±15 days)
A single bone biopsy will be obtained from the iliac crest, following tetracycline double-labeling, in 
a subset of subjects (from US sites only). The biopsy should be scheduled to be performed 
26 weeks after the first administration of IMP. Biopsies will be obtained from approximately 
20 subjects to obtain approximately 15 evaluable biopsy specimens.
The following evaluations will be performed:
•
Check subject discontinuation criteria.
•
Record physical examination outcome (changes from the previous visit).
•
Record vital signs.
•
Record triplicate 12-lead ECG.
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
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•
Ask the subject to complete the PGIC.
•
Ask the subject to complete the BPI interference scale.
•
Ask the subject to complete the PDI.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PASS.
•
Ask the subject to complete the CES-D.
•
Ask the subject to complete the WPAI: CRPS (US sites only).
•
Collect medical resources utilization and health economics data (US sites only).
•
Complete the assessment of the signs and symptoms of CRPS.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis.
•
Take blood (in the morning) for bone turnover marker evaluation.
•
For women of child-bearing potential allocated to treatment after the first 100 subjects have 
been allocated, perform a urine ß-HCG pregnancy test.
•
For all subjects allocated to treatment after the first 100 subjects have been allocated, 
collect subject trial card.
•
Perform bone imaging (DXA and MRI will be performed in a subset of approximately 
30 subjects [from US sites only]).
•
Record adverse events.
•
Collect tetracycline dosing diary from US subjects undergoing a bone biopsy.
11.1.3.5
Visit 10 (Week 39; ±15 days)
The following evaluations will be performed:
•
Check subject discontinuation criteria.
•
Record physical examination outcome (changes from the previous visit).
•
Record vital signs.
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Ask the subject to complete the PGIC.
•
Ask the subject to complete the BPI interference scale.
•
Ask the subject to complete the PDI.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PASS.
•
Ask the subject to complete the CES-D.
•
Complete the assessment of the signs and symptoms of CRPS.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis.
•
Take blood (in the morning) for bone turnover marker evaluation.
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•
Record adverse events.
11.1.3.6
Visit 11 (Week 52; ±15 days)
The following evaluations will be performed:
•
Record physical examination outcome (changes from the previous visit).
•
Record vital signs.
•
Record triplicate 12-lead ECG.
•
Record concomitant medications and therapies.
•
Ask the subject to complete pain intensity assessments.
•
Ask the subject to complete the PGIC.
•
Ask the subject to complete the BPI interference scale.
•
Ask the subject to complete the PDI.
•
Ask the subject to complete the EQ-5D-5L.
•
Ask the subject to complete the PASS.
•
Ask the subject to complete the CES-D.
•
Ask the subject to complete the WPAI: CRPS (US sites only).
•
Collect medical resources utilization and health economics data (US sites only).
•
Complete the assessment of the signs and symptoms of CRPS.
•
Take blood for safety laboratory.
•
Collect urine for central safety laboratory urinalysis.
•
Take blood (in the morning) for bone turnover marker evaluation.
•
Perform a urine ß-HCG pregnancy test (for women of child-bearing potential).
•
Collect subject trial card.
•
Record adverse events.
11.2
Examination hierarchy and time windows
Electrocardiograms should be taken before invasive procedures. When practical, blood samples for 
safety laboratory evaluation should be taken after all non-invasive procedures (including 
completion of questionnaires) have been finished. During the Treatment Period, procedures should 
be performed prior to administration of IMP, except where indicated.
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.
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.
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See the guidance in the investigator’s brochure for precautions and the handling of emergencies.
11.3.2
Meals and fluid intake restrictions
Blood samples for bone turnover markers should be obtained in the morning after an overnight fast 
(at least 8 hours) at Visit 2 and at Visits 6, 7, 8, 9, 10, and 11.
Light meals are allowed after sampling for blood turnover markers and may be provided before 
and/or after IMP infusions at Visit 2, Visit 3, Visit 4, and Visit 5.
Fluid intake is recommended prior to and during the infusions. Subjects must be well hydrated prior 
to the start of infusions.
Subjects undergoing bone biopsy should cease calcium supplements and avoid milk and dairy 
products during administration of tetracycline.
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 1.6). 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.
The card will be collected at the last visit.
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11.5
Provisions of any additional care of subject after trial termination
Subjects will be encouraged to continue daily calcium and vitamin D supplementation for 1 year 
from the start of treatment.
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 is estimated to be less than 180 mL during the trial 
(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). The volume of blood 
taken may vary due to trial site requirements.
Sampling times are given in the schedule of events (Section 1.6).
Table 3:
Planned approximate blood sampling volumes collected from each subject
Test
Unit volume of blood
Number of samples
Total
Sampling for bone turnover markers
7.5 mL
7
52.5 mL
Sampling for central safety laboratory monitoring:
Hematology
3 mL
11
33 mL
Clinical chemistry a
5 mL
11
55 mL
Parathyroid hormone
3 mL
11
33 mL
Total
40
173.5 mL
The volume of blood taken may be individually variable due to local practices and the potential need for resampling.
a) Includes vitamin D testing.
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, and height.
Body weight and body mass index will be determined at all trial visits and are listed with vital signs 
instead of demographic data (Section 12.3.2).
12.2.2
Prior and concomitant medication or therapies
All medication requiring prescriptions (including oral contraceptives), over-the-counter medication, 
and therapies used within 3 months prior to enrollment and up to the end of the trial must be 
recorded in the CRF. Any change in dosage, regimen, or route, must be recorded in the CRF as a 
new entry.
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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 CRF (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 CRF.
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 (especially hand or foot), with or without proximal spread, should 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 CRF. 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. Diagnosis of CRPS 
involving an atypical body part (e.g., trunk, breasts, pelvic regions, lower back, face) 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 active range of motion, or weakness) (see Section 18.4).
Medical history related to CRPS must include the following: date and description of precipitating 
event (e.g., type of trauma, surgery; 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, 
and date of CRPS diagnosis. 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 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 predispose to risk of 
medication-related ONJ.
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 the Enrollment Visit 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 CRF:
•
Cocaine, MDMA (3,4-methylendioxy methamphetamine, ecstasy), amphetamines, 
cannabinoids.
Subjects who are receiving stable doses of prescribed medications containing amphetamines, 
benzodiazepines, or opioids may participate (according to the judgment of the investigator upon 
approval by the sponsor) even if the test is positive.
12.3
Collection of safety data
The following safety data will be collected: adverse events, vital signs, 12-lead ECGs, safety 
laboratory parameters, physical examination findings, urine ß-HCG pregnancy test outcome, and 
bone biopsies for histology and histomorphometry (in a subset of subjects).
For the timings of assessments, see the schedule of events (Section 1.6).
Clinically relevant abnormal values (investigator’s judgment) must be recorded as adverse events.
12.3.1
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.
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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 
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”.
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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 1.6.
All adverse events reported spontaneously by subjects at any time point will also be documented. 
All adverse events will be documented in the CRF 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.
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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 
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
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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).
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. 
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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 IMP(s).
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.
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.
12.3.2
Vital signs
The vital signs comprise systolic and diastolic blood pressure, pulse rate, respiratory rate, body 
weight and body mass index.
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Body weight will be measured in light clothes.
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.
12.3.3
Twelve-lead electrocardiogram
All ECGs will be recorded in triplicate (3 readings in rapid succession no more than 2 minutes 
apart). 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).
Electrocardiogram parameters will include heart rate and the following ECG intervals (measured or 
derived); QRS, PR, RR, QT, corrected QT interval (to Bazett’s formula; QTcB), and QTcF. The 
ECG central reader will provide an assessment and interpretation of any waveform abnormalities 
and other findings (e.g., conduction defects). Both the locally obtained ECG and the report from the 
ECG central reader must be reviewed by the investigator; the investigator will be responsible for 
determining the clinical significance of any abnormality. Results will be documented by the 
investigator as “normal”, “abnormal, clinically not relevant”, or “abnormal, clinically relevant”.
For decisions pertaining to subject exclusion or discontinuation of IMP due to QT prolongation, the 
average QTcF, calculated from 3 successive ECGs, will be used. Values from the ECG central 
reader will supersede interval values reported by the ECG machine.
Electrocardiograms with poor quality tracings, artifacts or doubtful findings should be repeated, if 
possible.
The original ECG recordings will be kept at the site.
12.3.4
Continuous real-time ECG monitoring
Continuous real-time ECG monitoring, which may be performed by telemetry, will be performed at 
the infusion visits (Day 1, Day 4, Day 7, and Day 10), starting at least 30 minutes prior to the 
beginning of each infusion and for up to at least 30 minutes after the end of each infusion. 
Continuous real-time ECG monitoring must be performed by a qualified person. Personnel trained 
in advanced cardiopulmonary resuscitation must be on site and readily available to treat any 
potential cardiac rhythm disturbances.
Electrocardiogram machines may be used for continuous real-time ECG monitoring.
12.3.5
Safety laboratory
Laboratory tests (except for urine dipsticks for urine drugs of abuse testing and urine pregnancy 
testing) will be performed by a central safety laboratory. At Visit 2, Visit 3, Visit 4, and Visit 5, in 
addition to taking blood and urine samples for evaluation at the central safety laboratory, an 
assessment of urinary ACR will be performed prior to infusion using a semi-quantitative dipstick.
The use of any clinical laboratory facility other than the designated central safety laboratory is not 
allowed. The only exception is in the case of an emergency where the investigator requires the 
results quickly.
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A table of the reference ranges for each of the laboratory parameters measured with a description of 
the methods will be provided by the central safety laboratory before the trial start and is to be filed 
in the investigators site file.
Changes in the reference ranges or in the methodology during the course of the trial are to be 
communicated by the central safety laboratory to the sponsor who will inform the investigators.
Alert ranges for specific laboratory parameters will be provided by the sponsor to the central safety
laboratory. Any laboratory value within these alert ranges will be immediately reported to the 
investigator.
The sites will be provided with a manual by the central laboratory specifying the specimen 
collection, preparation, packaging, and transport of all clinical laboratory tests required by this 
protocol.
Throughout the clinical part of the trial, the investigator must provide a comment in the CRF 
regarding the clinical relevance of any laboratory values outside of the sponsor-defined alert range. 
Any abnormal laboratory result considered clinically relevant will be followed until it reaches a 
satisfactory resolution, becomes stable, or can be explained by other causes (e.g., concurrent 
condition or medication), and clinical judgment indicates that further evaluation is not needed. The 
printout of the laboratory values will be stored with the source data. 
Data will be transferred from the central safety laboratory to the sponsor electronically.
The following tests will be performed:
Hematology panel
Hemoglobin
Mean cell volume (MCV)
Hematocrit
Platelet count
Mean cell hemoglobin (MCH)
Red blood cell (RBC) count
Mean cell hemoglobin concentration 
(MCHC)
White blood cell (WBC) count with differential count a
a) Includes neutrophils, lymphocytes, monocytes, basophils, eosinophils (absolute count and percent).
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Clinical chemistry panel
Alanine aminotransferase (ALT)
Lactic acid dehydrogenase (LDH)
Albumin 
Lipase
Alkaline phosphatase 
Magnesium
Aspartate aminotransferase (AST)
Parathyroid hormone
Bicarbonate
Phosphorus
Blood urea nitrogen (BUN)
Potassium
Calcium (measured and albumin-corrected)
Sodium
Chloride
Total bilirubin
Cholesterol
Total protein
Creatine phosphokinase
Triglycerides
Creatinine (serum)
Uric acid
Gamma-glutamyl transferase (GGT)
Vitamin D
Glucose
The eGFR will be calculated using the 2009 CKD-EPI creatinine equation (Levey et al. 2009).
Urinalysis panel
Dipstick
Quantitative Analysis
Albumin creatinine ratio (ACR) a
Albumin (microalbumin)
pH
Calcium
Glucose
Creatinine
Urobilinogen 
Calculated urinary ACR
Blood (erythrocytes)
Leukocyte esterase
Protein
Ketone
Bilirubin
Nitrite
a) Determined at site on infusion days only.
If the dipstick test is positive (except for glucose or ketones, and blood/leucocytes in menstruating 
subjects), a microscopic examination of urine sediment will be performed to determine the presence 
of red blood cells, white blood cells, epithelial cells, crystals, casts, and bacteria.
If either alanine aminotransferase or aspartate aminotransferase are more than 3-fold the upper limit 
of the central laboratory reference range, the laboratory test should be repeated within 72 hours. If 
elevated values are confirmed, 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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12.3.6
Physical examination
After treatment allocation, any clinically relevant changes from the previous visit for physical 
examination will be documented as adverse events.
12.3.7
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 CRF.
Additional pregnancy tests to those specified may be performed if required by local law or 
regulations.
12.3.8
Bone biopsy procedures
Iliac crest bone biopsies will be performed in a subset of trial subjects to assess the bone safety of 
neridronic acid 400 mg. Bone biopsies will be obtained from subjects participating at sites in the 
US. Subject eligibility may depend on proximity to clinical facilities where biopsies will be 
performed. Only a single biopsy will be obtained from each participating subject.
Subjects consenting to bone biopsy will undergo double-tetracycline labeling starting up to 40 days 
prior to the scheduled biopsy procedure at month 6. Oral tetracycline hydrochloride will be given 
for an initial 3-day cycle, followed by a 14-day interval without tetracycline, and by a second 3-day 
cycle of oral tetracycline. The dose of tetracycline will be 250 mg 4 times a day for 3 days. Subjects 
will be instructed to take each dose 1 hour to 2 hours before a meal or 2 hours after a meal. The 
subjects are to be instructed to record the intake of tetracycline in a tetracycline dosing diary. 
Subjects should not take oral calcium supplements on days they are taking tetracycline. If a dose of 
tetracycline is skipped/missed, it should be taken as soon as possible or with the next scheduled 
dose, and the information regarding the missed/skipped dose should be entered into the subject’s
file.
Site staff must phone each subject several times during the scheduled tetracycline dosing in order to 
ensure good compliance with the dosing schedule. The tetracycline dosing diary will be verified for 
dosing schedule compliance before performing the iliac crest bone biopsy.
An iliac crest biopsy will be obtained 5 days to 14 days after the last dose of tetracycline according
to procedures of Dempster and Shane (1995). Prior to the bone biopsy, subjects may receive 
optional intravenous sedation. The site of the biopsy will be numbed with a local anesthetic (e.g., 
xylocaine, lidocaine) to minimize discomfort. 
Biopsies will be performed using a Bordier type biopsy needle with a minimum internal diameter of 
7.5 mm to ensure an adequate sample size. Evaluable biopsies must contain inner and outer cortical 
plates with intervening cancellous bone. The biopsy will be performed only by investigators who 
are skilled and experienced in this procedure. For subjects with lower limb CRPS, the biopsy must 
be taken from the hip contralateral to the CRPS-affected limb. 
Subjects will return to the bone biopsy center 7 days to 10 days after the bone biopsy to have 
stitches removed.
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The following information must be recorded in the CRF:
•
Confirmation that informed consent was obtained to perform biopsy.
•
Dates of tetracycline dosing and confirmation that the dose was taken.
•
Date of biopsy and confirmation that biopsy was taken.
Bone biopsies will be processed for histology and for measurement of static and dynamic 
histomorphometry according to standard procedures (Recker et al. 2011; Dempster et al. 2013). 
Qualitative histological analysis will include assessment for evidence of bone mineralization 
abnormalities (i.e., osteomalacia), woven bone, marrow fibrosis, abnormalities in cellular 
components, or other abnormalities. Unstained sections will be viewed by fluorescence microscopy 
and will be used for determination of dynamic histomorphometry parameters using tetracycline-
based indices. The tetracycline dosing diary data on tetracycline intake recorded by the subjects will 
be transferred to the histomorphometry laboratory. Quantitative histomorphometric analysis will 
include assessment of static parameters (e.g., osteoid thickness, osteoid surface, osteoid volume, 
and dynamic parameters (e.g., mineral apposition rate, mineralizing surface, bone formation rate, 
mineralization lag time, osteoid maturation time, and activation frequency); all indices will be 
calculated and expressed according to the recommendations of the American Society for Bone and 
Mineral Research (Dempster et al. 2013).
Data from the histomorphometry measurements and standard histologic examination will be 
transferred electronically to the data management center using a secure method at predefined 
intervals during the trial.
12.4
Collection of efficacy data
The following efficacy data will be collected: pain intensity, PGIC, BPI interference scale, PDI, 
EQ-5D-5L, PASS, CES-D, and CRPS Severity Score.
For the timings of assessments, see the schedule of events (Section 1.6).
12.4.1
Pain intensity
Pain intensity assessments will be captured in an electronic patient reported outcome system kept at 
the sites. Subjects will be asked to record their current, worst, and average CRPS-related pain 
intensity at each visit using an 11-point NRS (from 0 = “no pain” to 10 = “pain as bad as you can 
imagine”).
0
1
2
3
4
5
6
7
8
9
10
No 
pain
Pain as bad as you can 
imagine
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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.”
Worst pain assessment
Subjects will be asked to record their worst 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 your pain at its worst during 
the last 24 hours.”
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.”
12.4.2
Patient Global Impression of Change
The PGIC will be assessed at Visit 7 through Visit 11. 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.
12.4.3
Brief Pain Inventory interference scale
Subjects will complete the BPI Interference Scale questionnaire (Section 18.3.2) at Visit 2 and 
Visit 7 through Visit 11. This is a multi-item scale measuring the impact of pain on functioning and 
well-being. The 7 pain interference items: general activity, walking, work, mood, enjoyment of life, 
relations with others, and sleep, are each rated on a 0 to 10 scale using a 24-hour recall period, with 
0 indicating “does not interfere” and 10 indicating “completely interferes”. The total Pain 
Interference Score is calculated by adding the scores for the 7 questions and dividing by 7. This 
gives an interference score with a range from 0 to 10. This mean can be calculated if more than 50% 
(four of seven) of the total items have been completed on a given administration. A 1 point decrease 
in the BPI Interference Scale score is generally considered as the minimum clinically important 
decrease (Dworkin et al. 2008).
12.4.4
Pain Disability Index
The PDI questionnaire (Section 18.3.3) will be completed by all subjects at Visit 2 and Visit 7 
through Visit 11. The PDI questionnaire includes questions related to pain-related disability in 
7 categories: family/home responsibilities, recreation, social activity, occupation, sexual behavior, 
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self-care, and life-support activities. For each of the 7 categories, the subjects are asked to rate on an 
11-point NRS the level of disability they typically experience. The PDI is calculated as the sum of 
the 7 categories, for a minimum value of 0 and maximum value of 70. Higher scores indicate 
greater disability due to pain. In other chronic pain conditions, a decrease of 8.5 points to 9.5 points 
in the PDI was considered to be clinically important (Soer et al. 2012).
12.4.5
EuroQoL-5 dimension 5 level
The EQ-5D-5L health questionnaire (Section 18.3.4) will be completed by all subjects at Visit 2 and 
Visit 7 through Visit 11. 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.
12.4.6
Pain Anxiety Symptom Scale
The PASS questionnaire (Section 18.3.5) will be completed by all subjects at Visit 2 and Visit 7 
through Visit 11. The PASS questionnaire consists of 20 items designed to assess 4 aspects of pain-
related anxiety: cognitive anxiety, escape-avoidance behaviors, fear of pain, and physiological 
symptoms of anxiety. Subjects rate each item in terms of frequency, from 0 (never) to 5 (always). 
The total score is calculated as the sum of ratings, with values ranging from 0 to 100; higher scores 
indicate higher levels of pain-related anxiety.
12.4.7
Center for Epidemiological Studies Depression Scale
The CES-D questionnaire (Section 18.3.6) will be completed by all subjects at Visit 2 and Visit 7 
through Visit 11. The CES-D is a short questionnaire designed to measure depressive 
symptomatology in the general population. The 20 items of the scale are symptoms associated with 
depression which have been used in previously validated longer scales. Subjects are asked to rate 
each item from “rarely or none of the time (less than 1 day)” to “most or all of the time (5 to 
7 days)” during the last week. Response scores for all questions except 4, 8, 12, and 16 are: 
<1 day = 0; 1-2 days = 1; 3-4 days = 2; 5-7 days = 3. For questions 4, 8, 12, and 16, the scoring is 
reversed. The total CES-D score is calculated as the sum of scores for all 20 questions and has a 
range of 0 to 60. A score over 21 indicates the possibility of major depression.
12.4.8
CRPS Severity Score
Signs and symptoms of CRPS (Section 18.4) will be assessed by the investigator at Visit 2 
(baseline) and Visit 7 through Visit 11 and recorded using the electronic patient reported outcome 
system. Subjects will be queried on 8 self-reported symptoms (queried yes or no): allodynia and/or 
hyperalgesia; temperature asymmetry; skin color asymmetry; sweating asymmetry; asymmetric 
edema; dystrophic changes; motor changes; and decreased active range of motion. 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 
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changes. 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).
12.5
Collection of pharmacodynamic data
12.5.1
Bone turnover markers
Samples taken for bone turnover marker evaluation should be collected in the morning after an 
overnight fast (at least 8 hours) due to diurnal variation and effects of a meal. Serum concentrations 
will be determined for CTX, BAP, and PINP.
Specific procedures for preparation of serum samples and storage and shipment will be provided to 
the sites.
12.5.2
Bone densitometry and magnetic resonance imaging
Subjects selected from sites in the US for inclusion in the imaging subset must have distal limb 
involvement (i.e., CRPS signs and symptoms located in the hand, foot, wrist or ankle), with or 
without proximal spread, as described in Section 12.2.3.1. Distal localization is required due to 
specific MRI coils intended for selected imaging of wrist/hand and ankle/foot. Subjects with 
metallic implants or other contraindications to MRI, including claustrophobia reactions, will be 
excluded.
All imaging will be performed by trained technicians at selected imaging facilities in reasonable 
proximity to trial sites.
The following information must be recorded in the CRF:
•
Confirmation that informed consent was obtained to perform bone imaging.
•
Dates of DXA performance (baseline and 6-month assessments).
•
Dates of MRI performance (baseline and 6-month assessments).
•
Limb/region where DXA and MRI were performed.
Data from the bone imaging assessments will be transferred electronically to the data management 
center using a secure method at predefined intervals during the trial.
Bone densitometry
Dual energy x-ray absorptiometry of the CRPS-affected limb, contralateral (unaffected) limb, and 
lumbar spine. The same DXA machine must be used for baseline and 6-month scans for a particular 
subject. Lumbar spine scans will include L1 through L4. DXA scans will be submitted to and 
analyzed by the central imaging vendor. A manual will be provided by the central imaging vendor 
with specific instructions for acquisition of scans as well as performance of instrument quality 
control.
Bone mineral content and bone area will be used to determine areal BMD in the CRPS-affected 
limb, contralateral limb and lumbar spine. T scores will be determined for the lumbar spine. Change 
Pattern analysis will be performed comparing ROIs from the CRPS-affected and contralateral 
extremities. The principal outcome measure for this analysis will be change from baseline in areal 
BMD of ROIs in the CRPS-affected limb, relative to the contralateral limb.
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Magnetic resonance imaging
High-resolution, three-dimensional MRI will be performed at baseline (during the enrollment 
period) and approximately 6 months after the start of treatment. Magnetic resonance imaging will 
be performed using 1.5 or 3 Tesla MRI instrument at facilities in reasonable proximity to trial sites. 
T1 and T2-weighted images will be acquired of the CRPS-affected and contralateral limbs. No 
gadolinium contrast agent will be used. Imaging will be performed on sagittal, coronal, and 
transverse planes, with appropriate field of view to encompass the CRPS-affected limb. Bone 
marrow lesions will be identified as areas of increased signal intensity on fat-suppressed T2-
weighted images. Volume of all bone marrow lesions in the CRPS-affected and contralateral limb 
will be determined by a radiologist or appropriately trained technician who is blinded to the affected 
limb and treatment sequence (pre- or post-treatment). Pattern analysis will be performed comparing 
ROIs from the CRPS-affected and contralateral extremities. The outcome measure will be change 
from baseline in total volume of bone marrow lesions in the CRPS-affected limb, relative to the 
contralateral limb. 
12.6
Collection of health economics outcome and work productivity data
(US sites only)
12.6.1
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 18.3.7).
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 at Visit 2, at Week 26, and at Week 52.
12.6.2
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 Visit 2, at Visit 9, and at Week 52.
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 CRF by the investigator.
12.7
Appropriateness of measurements
As CRPS is a rare, poorly understood chronic pain syndrome condition with very few adequate and 
well-controlled trials having been conducted, none of the proposed outcome measures for this trial 
have been formally validated in this population. Consequently, outcome measures selected for this 
trial were based on clinical outcome measures used in interventional trials in more common chronic 
pain conditions.
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Safety assessments
Bone histology and histomorphometry
Bone histology and histomorphometry, performed on transiliac bone biopsy specimens, are 
established and standardized procedures to assess for the presence of bone abnormalities such as 
osteomalacia (Dempster et al. 2013). Clinical evaluation of bone histology and histomorphometry is 
required by the FDA for evaluation of the safety of new drugs and biologic products for treatment 
of osteoporosis, including bisphosphonates. Effects of neridronic acid on bone histology and 
histomorphometry was previously evaluated in biopsies from 14 patients with Paget’s disease 
receiving neridronic acid 250 mg (50 mg/day for 5 days; McCloskey et al. 1987; Atkins et al 1987). 
Neridronic acid improved indices of bone turnover in pagetic bone, and normal bone mineralization 
and bone formation were observed in biopsies from healthy, non-pagetic bone in the iliac crest.
Efficacy assessments
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).
On the basis of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials 
(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). Current, average and 
worst pain intensity will be assessed, with average and worst pain assessed using a 24-hour recall.
An electronic subject-reported outcome will be used to ensure data integrity by only allowing 
subjects to access the tool. Electronic diaries 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).
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).
Brief Pain Inventory interference scale
The BPI interference scale shows reliability and validity for chronic pain and is a core outcome 
measure for the assessment of the impact of chronic pain on activities of daily living (Dworkin et al. 
2005).
Pain Disability Index
The PDI is a brief instrument that was developed to assess pain-related disability, providing 
information that complements the assessment of physical impairment.
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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.
Pain Anxiety Symptom Scale
The 20-item PASS, based on the original 40-item PASS, was developed by McCracken and 
Dhingra (2002) to assess anxiety related specifically to pain in clinical and research contexts. It 
shows strong internal consistency, reliability, and good predictive and construct validity.
Center for Epidemiological Studies Depression Scale
The CES-D scale was tested in household interview surveys and in psychiatric settings. It was 
found to have very high internal consistency and adequate test-retest repeatability. Validity was 
established by patterns of correlations with other self-report measures, by correlations with clinical 
ratings of depression, and by relationships with other variables which support its construct validity. 
Reliability, validity, and factor structure were similar across a wide variety of demographic 
characteristics in the general population samples tested (Radloff 1977).
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 
selected markers are known to be responsive to and associated with the mechanism of action of 
bisphosphonates.
Bone densitometry and magnetic resonance imaging
Bone abnormalities, including regional osteoporosis/osteopenia on X-rays and osteolytic lesions 
identified by uptake of radiolabelled bisphosphonate and triple-phase bone scintigraphy, have been 
described in patients with CRPS (O’Donoghue et al. 1993; Veldman et al 1993; Wüppenhorst et al. 
2010; Ringer et al. 2012). In addition, bone marrow lesions, defined as ill-defined areas of 
hyperintense signal intensity on T2- or intermediate-weighted fat-suppressed and short-tau 
inversion recovery magnetic resonance images, have also been reported in CRPS (Crozier et al. 
2003, Varenna et al. 2013) and are thought to overlap with regions of high bone turnover.
Dual-energy X-ray absorptiometry and MRI are established, noninvasive imaging methods that 
have been used extensively in trials investigating bisphosphonates for treatment of osteoporosis, 
osteoarthritis, and other conditions.
Medical resources utilization and health economics data collection
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, 
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psoriasis, irritable bowel syndrome, ankylosing spondylitis, and Crohn’s disease. 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.
12.8
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 will be ensured by capturing 
the information in an electronic patient reported outcome system at the sites.
Relevant deviations from the protocol will be documented and described in the integrated clinical 
trial report.
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 CRFs to record information required by 
the protocol.
All CRF 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 CRF system. The collected data will 
reside on servers of the CRF 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 subjects CRF, the CRF must be signed electronically by the investigator. With 
the investigator’s signature it is confirmed that the data in the CRF are checked, complete, accurate, 
and in alignment with the source data. Changes to the CRF after initial signing by the investigator 
need re-signing.
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With database lock, the edit rights to the CRFs will be removed but the investigator will retain 
access to view the CRFs 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.
13.1.1
Subject tetracycline dosing diary
A subject tetracycline dosing diary will be used to record the intake of tetracycline in US subjects 
undergoing a transiliac bone biopsy. These data will be supplied to the histomorphometry 
laboratory for incorporation into the bone biopsy record.
13.2
Subject reported outcomes
Subject reported outcomes will be collected using a validated electronic patient reported outcome 
system including audit trail.
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.
The electronic patient reported outcome 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.
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 CRF or subject reported outcome, but requested per protocol (e.g., 
safety laboratory data, ECG data, bone biopsy data, bone imaging 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 
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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 CRF and not in other 
documents. When this occurs, the CRF is considered to be the source document. Data expected to 
be only recorded in the CRF 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 CRF 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.
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.
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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.
Subset of subjects for bone biopsies
The sample size is not based on statistical considerations; bone biopsy specimen evaluation will 
identify qualitative bone abnormalities such as osteomalacia as well as quantitative indicators of 
impaired mineralization.
Subset of subjects for bone densitometry and magnetic resonance imaging
The sample size is not selected based on statistical considerations. Results from this subset of 
subjects are considered to be sufficient to demonstrate feasibility and explore outcomes of these 
assessments in trials of neridronic acid in CRPS.
14.1.2
General description of statistical analyses
The statistical analysis of this trial will be performed as described and summarized in the protocol. 
Full details of the planned statistical analyses will be described in the trial statistical analysis plan.
The statistical analysis of this trial will be planned, performed, and reported by sponsor personnel or 
by authorized sponsor delegates.
As this is a single-arm trial, no treatment comparisons will be conducted, but development from 
baseline over time will be investigated. All analyses in this trial will be of exploratory nature. No 
statistical testing of inference is planned in this trial. There will be no multiplicity adjustment for 
any of the analyses. All confidence intervals used to describe the data will be determined using a 
95% confidence level.
Collected and derived data will be listed.
Summary statistics and graphical methods will be used to describe parameters/variables.
The following descriptive statistics will be produced on the basis of the nature of the relevant 
variable:
•
For continuous variables: number of non-missing observations, arithmetic mean, standard 
deviations, minimum, first quartile, median, third quartile, and maximum.
•
For categorical variables: absolute and relative frequencies and percentages.
14.1.3
Analysis populations (analysis sets)
The analysis populations are defined in 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.
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14.1.5
Analysis of demographic data and other baseline characteristics
Demographic data, baseline characteristics, medical history, concomitant medications, and exposure 
will be summarized descriptively for the Safety Set.
14.1.6
Analysis of safety data
14.1.6.1
Adverse events
A definition of adverse event is given in Section 12.3.1.
The original terms recorded in the CRF 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.
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 period are also considered TEAEs.
Treatment emergent adverse events will be summarized for each treatment group by System Organ 
Class and Preferred Term. Additional summaries by time to onset, duration, intensity, relationship 
to the IMP, outcome, expectedness, and countermeasures will also be created. To account for the 
differences in the planned trial duration of the subjects in this trial, an analysis of exposure-adjusted 
incidence rates will be done in addition to the analysis of crude incidence rates.
Subjects with SAEs will be summarized and additionally listed. Special attention will be given to 
those subjects who discontinue treatment due to an adverse event or who experience a severe or 
SAE.
The incidences and incidence rates of all adverse events will be summarized descriptively.
Permanent discontinuations from treatment due to adverse events will be summarized descriptively. 
The distribution of time to onset of any TEAE will be summarized using time-to event methods. A 
graphical display using Kaplan-Meier methods displaying subjects at risk per time point will also be 
produced.
14.1.6.1.1
Analysis of the primary endpoint
The primary endpoint of this trial is a binary endpoint assessing whether or not a subject 
experienced any TEAE. 
14.1.6.2
Safety laboratory values, vital signs, 12-lead ECG
Safety laboratory values, vital signs, and 12-lead ECG will be summarized descriptively.
Baseline will be the value collected on Day 1 (Visit 2) prior to first administration of IMP.
Sponsor-defined alert ranges will be defined for selected parameters. Subjects with values outside 
of sponsor-defined alert ranges will be summarized. Subjects with abnormal values will be 
tabulated and listed separately.
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14.1.6.3
Bone biopsy assessments
The occurrence of histomorphometric evidence of osteomalacia, defined as osteoid thickness 
>12.5 µm (corrected for obliquity) and mineralization lag time >100 days (Dempster et al. 2013) 
will be derived for each assessed subject. All bone biopsy parameters will be descriptively 
summarized for the Bone Biopsy Set.
14.1.7
Analysis of efficacy data
The analysis of all efficacy endpoints will be exploratory and will be summarized using descriptive 
statistics unless stated otherwise. Analyses will be performed on all post baseline measurements.
Handling of missing data
Missing data will not be imputed in this trial. The number of missing data will be included in all 
descriptive summaries.
An MMRM will be conducted on the observed values of the change in current pain intensity score. 
An MMRM leads to unbiased estimates if the missingness mechanism is missing-at-random. Due to 
the long-acting effect of neridronic acid, missing-at-random is considered a clinically plausible 
assumption. The MMRM in this trial will include the covariate baseline pain intensity and the 
factors pooled site and visit as fixed effects, and subject as random effect. An unstructured 
covariance matrix will be used to model the covariance structure. Least squares means, standard 
errors, and 95% confidence intervals for the change from baseline will be obtained.
14.1.8
Analysis of pharmacodynamic data
Bone turnover markers including changes from baseline will be descriptively summarized for the 
Pharmacodynamic Set. Baseline is defined by the value on Day 1 (Visit 2).
14.1.9
Analysis of bone imaging data
Bone densitometry and magnetic resonance imaging parameters including changes from baseline 
will be descriptively summarized for the Bone Imaging Set. Baseline is defined by the value at 
Visit 1.
14.1.10
Analysis of health economics outcome and work productivity data
Medical resources utilization and health economics data will be descriptively summarized.
14.1.11
Interim analysis
Not applicable.
14.1.12
Ad hoc meta-analyses
Data collected in this trial may be used for ad hoc meta-analyses. These meta-analyses will be 
planned, performed, and reported by sponsor personnel or by authorized sponsor delegates in 
accordance with sponsor SOPs.
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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 investigators, 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.
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.
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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 
site(s) 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 should 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 
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 investigator before they are submitted for publication or public disclosure. 
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Neither the sponsor nor the coordinating investigator has the right to prohibit publication or public 
disclosure unless it can be shown to affect possible patent rights.
16.6
Trial results reporting
A final report integrating clinical, pharmacodynamics 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.
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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Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, et al. 
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Harden RN, Bruehl S, Perez SG, Birklein F, Marinus J, Maihofner C, et al. Validation of proposed 
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Harden RN, Bruehl S, Perez RS, Birklein F, Marinus J, Maihofner C, et al. Development of a 
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Harden RN, Oaklander AL, Burton AW, Perez RS, Richardson K, Swan M, et al. Complex regional 
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Hernandez JD, Wesseling K, Pereira R, Gales B, Harrison R, Salusky IB. Technical approach to 
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Jung K, Lein, M. Bone turnover markers in serum and urine as diagnostic, prognostic and 
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Khosla S, Bilezikian JP, Dempster DW, Lewiecki EM, Miller PD, Neer RM, et al. Benefits and 
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turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for 
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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: Jul 2012
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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pY,1029I20
PATIENT GLOBAL IMPRESSION OF CHANGE 
(PGIC)
Since the start of the study, my overall status Is
done box only
(I) K Very Much Improved
[2) K Much Improved
[3) K Minimally Improved
[4] K No Change
[5) K Minimally Worse
[6) K Much Worse
[7] K Very Much Worse
(US/English)
6G1G USNEnykh - 
Original mean
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18.3.2
Brief Pain Inventory interference scale
Circle the one number that describes how, during the past 24 hours, pain has interfered with your:
A. General Activity
0
1
2
3
4
5
6
7
8
9
10
Does not 
interfere
Completely 
interferes
B. Mood
0
1
2
3
4
5
6
7
8
9
10
Does not 
interfere
Completely 
interferes
C. Walking Ability
0
1
2
3
4
5
6
7
8
9
10
Does not 
interfere
Completely 
interferes
D. Normal Work (includes both work outside the home and housework)
0
1
2
3
4
5
6
7
8
9
10
Does not 
interfere
Completely 
interferes
E. Relations with other people
0
1
2
3
4
5
6
7
8
9
10
Does not 
interfere
Completely 
interferes
F. Sleep
0
1
2
3
4
5
6
7
8
9
10
Does not 
interfere
Completely 
interferes
G. Enjoyment of life
0
1
2
3
4
5
6
7
8
9
10
Does not 
interfere
Completely 
interferes
DMS version: 
 
ID: 
 
5.0
1226379


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 88 of 128
DMS version 5.0
17 Nov 2017
18.3.3
Pain Disability Index
DMS version: 
 
ID: 
 
5.0
1226379
Pain Disability Index
Pain Disability Index: The rating scales below are designed to measure the degree to which
aspects of your life are disrupted by chronic pain. In other words, we would like to know how
much pain is preventing you from doing what you would normally do or from doing it as well as
you normally would. Respond to each category indicating the overall impact of pain in your life,
not just when pain is at its worst.
For each of the 7 categories of life activity listed, please circle the number on the scale that
describes the level of disability you typically experience. A score of 0 means no disability at all,
and a score of 10 signifies that all of the activities in which you would normally be involved have
been totally disrupted or prevented by your pain.
Family/Home Responsibilities: This category refers to activities of the home or family. It
includes chores or duties performed around the house (e.g. yard work) and errands or favors for
other family members (e.g. driving the children to school).
No Disability 0 1 
. 2 . 3 . 4 . 5 . 6 . 7 . 8 . 9  . 10 . Total Disability
Recreation: This category includes hobbies, sports, and other similar leisure time activities.
No Disability 0 . 1 .2 . 3 . 4 . 5 . 6 . 7 . 8 . 9  . 10_ Total Disability
Social Activity: This category refers to activities, which involve participation with friends and
acquaintances other than family members. It includes parties, theater, concerts, dining out, and
other social functions.
No Disability 0 . 1 . 2 .3 . 4 . 5 . 6 . 7 .8 .9  . 10_. Total Disability
Occupation: This category refers to activities that are part of or directly related to one's job. This
includes non-paying jobs as well, such as that of a housewife or volunteer.
No Disability 0 . 1 .2 . 3 . 4 . 5 . 6 . 7 . 8 . 9  . 10_. Total Disability
Sexual Behavior: This category refers to the frequency and quality of one's sex life.
No Disability 0 . 1 .2 . 3 . 4 . 5 . 6 . 7 . 8 . 9  . 10_. Total Disability
Self Care: This category includes activities, which involve personal maintenance and
independent daily living (e.g. taking a shower, driving, getting dressed, etc.)
No Disability 0 1 . 2 . 3 . 4 . 5 6 7 .8 . 9  . 10_ Total Disability
Life-Support Activities. This category refers to basic life supporting behaviors such as eating,
sleeping and breathing.
No Disability 0 1 
. 2 . 3 . 4 . 5 6 7 .8 .9 
 . 10 . Total Disability
Signature 
Please Print 
Date 


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 89 of 128
DMS version 5.0
17 Nov 2017
18.3.4
EuroQol-5 dimension 5 level
DMS version: 
 
ID: 
 
5.0
1226379
DIMS version: 1 A 
m: 102äd70
♦
EQ-5D-5L
Health Questionnaire
English version for the UK
UK (English) v.2 © 2W9 EuroQol Group. EQ-SDTM is a trade mark otthe EuroQol Group


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 90 of 128
DMS version 5.0
17 Nov 2017
DMS version: 
 
ID: 
 
5.0
1226379
D\45 version. I o 
ID: 1028200
Under each heading, please tick the ONE box that best describes your health TODAY
MOBILITY
I have no problems in walking about 
K
I have slight problems in walking about 
K
I have moderate problems in walking about 
K
I have severe problems in walking about 
K
I am unable to walk about 
K
SELF-CARE
I have no problems washing or dressing myself 
K
I have slight problems washing or dressing myself 
K
I have moderate problems washing or dressing myself 
K
I have severe problems washing or dressing myself 
K
I am unable to wash or dress myself 
K
USUAL ACTIVITIES (e.g. work, study, housework,
family or leisure activities)
I have no problems doing my usual activities 
K
I have slight problems doing my usual activities 
K
I have moderate problems doing my usual activities 
K
I have severe problems doing my usual activities 
K
I am unable to do my usual activities 
K
PAIN / DISCOMFORT
I have no pain or discomfort 
K
I have slight pain or discomfort 
K
I have moderate pain or discomfort 
K
I have severe pain or discomfort 
K
I have extreme pain or discomfort 
K
ANXIETY / DEPRESSION
I am not anxious or depressed 
K
I am slightly anxious or depressed 
K
I am moderately anxious or depressed 
K
I am severely anxious or depressed 
K
I am extremely anxious or depressed 
K
UK (English) v.2 0 
2009 EuroQol Group. EQ-5Um is a trade mark of the EuroQol Group


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 91 of 128
DMS version 5.0
17 Nov 2017
DMS version: 
 
ID: 
 
5.0
1226379
DMS version: I 4) 
ID: 1025200
The best health
you can imagine
100
• We would like to know how good or bad your health is
95
TODAY.
90
• This scale is numbered from 0 
to 100.
85
• 100 means the best health you can imagine.
0 means the worst health you can imagine.
80
• Mark an X on the scale to indicate how your health is TODAY.
= 
75
• Now, please write the number you marked on the
box below.
scale in the
70
65
60
55
YOUR HEALTH TODAY =
50
45
40
35
30
25
20
15
10
5
0
The worst health
you can imagine
3
UK (English) v.2 © 2009 EuroQol Group. EQ-5Dr"I is a trade mark of the EuroQol Group


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 92 of 128
DMS version 5.0
17 Nov 2017
18.3.5
Pain Anxiety Symptom Scale
DMS version: 
 
ID: 
 
5.0
1226379
PASS
Individuals who experience pain develop different ways to respond to that pain. We would like to know what you
do and what you think about when in pain. Please use the rating scale below to indicate how often you engage in
each of the following thoughts or activities. Circle any number from 0 (NEVER) to 5 (ALWAYS) for each item.
II
I think that if my pain gets too severe, it will never decrease 
III When I feel pain I am afraid that something terrible will happen 
111
I 
go immediately to bed when I feel severe pain 
Ill
I begin trembling when engaged in activity that increases pain 
Ill
I 
can't think straight when I am in pain 
s. 
I will stop any activity as soon as I sense pain coming on 
I
Pain seems to cause my heart to pound or race 
As soon as pain comes on I take medication to reduce it. 
II
When I feel pain I think that I may be seriously ill 
1111
 During painful episodes it is difficult for me to think of anything else besides the pain
• 
I 
avoid important activities when I hurt 
® 
When I sense pain I feel dizzy or faint 
® 
Pain sensations are terrifying 
NI
When I hurt I think about the pain constantly 
® 
Pain makes me nauseous (feel sick) 
® 
When pain comes on strong I think I might become paralyzed or more disabled 
® 
I 
find it hard to concentrate when I hurt 
n
I find it difficult to calm my body down after periods of pain 
® 
I 
worry when I am in pain 
Ill
I try to avoid activities that cause pain 
NEVER
ALWAYS
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5
0
1
2
3
4
5


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 93 of 128
DMS version 5.0
17 Nov 2017
18.3.6
Center for Epidemiological Studies Depression Scale
DMS version: 
 
ID: 
 
5.0
1226379
Depression Screening 
/VÄLUEOPTIONS®
Center for Epidemiologic Studies Depression (CES-D)
Scale Description:
The following scale was developed by the Center for Epidemiologic Studies (Radlof, 1977). The scale has been found
reliable (Alpha> .85) in previous research (Hann et. al., 1999). A Spanish version of this scale is also available.
Scale items:
Below is a list of some ways you may have felt or behaved. Please indicate how often you have felt this way during the
last week by checking the appropriate space. Please only provide one answer to each question.
During the past week:
Rarely or none of the
time (less than 1 day)
Sane ora little of
the time (1-2 days)
OCCaSIOnallyora
moderate amount of
time (3-4 days)
MOSt or all of the
time (5-7 days)
1.
I was bothered by things that usually
don't bother me.
2.
I did not feel like eating; my appetite
was poor.
3.
I felt that I could not shake off the blues
even with help from my family or
friends.
4.
I felt I wasjust as good as other people.
5.
I had trouble keeping my mind on what I
was doing.
6.
I felt depressed.
7.
I felt that everything I did was an effort.
8.
I felt hopeful about the future.
9.
I thought my life had been a failure.
10.
I felt fearful.
11.
My sleep was restless.
12.
I was happy.
13.
I talked less than usual.
14.
I felt lonely.
15.
People were unfriendly.
16.
I enjoyed life.
17.
I had crying spells.
18.
I felt sad.
19.
I felt that people disliked me.
20.
I could not get going.
Scoring:
Rarely
(Less than 1 day)
Some
(1-2 days)
Occasionally
(3-4 days)
Most
(5-7 days)
Questions 4, 8, 12, and 16
3
2
1
0
All other questions
0
1
2
3
The score is the sum of the 20 questions. Possible range is 0-60. If more than four questions are missing answers,
do not score the CES-D questionnaire. A score of 16 points or more is considered depressed.
References: 
Hann, D., Wnter, K., &Jacobsen, P. (1999) Measurement of depressive symptoms in cancer patients. Evaluation of the
Center for Epidemiological Studies Depression Scale (CES-D). Journal of Psychosomatic Research, 46,437-443.
Radloff, L.S. (1977). The CED-D scale: A self-report depression scale for research in the general population.
Applied Psychological Measurement, 1,385-401.


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 94 of 128
DMS version 5.0
17 Nov 2017
18.3.7
Work Productivity and Activity Impairment Questionnaire: CRPS
DMS version: 1.0 ID: 1245366
DMS version: 
 
ID: 
 
5.0
1226379
WORK PRODCCTI\TIT AND ACTIVTII IMPAIRMENT QUESTIONNAIRE:
COMPLEX REGIONAL PAIN SYNDROME VTRSIOr (WPAI:CRPS)
The following questions ask about the effect of your CRPS on your ability to work and perform regular daily
activities. Please fit in the blanks or circle a number, as indicated.
1) Are you currently employed (working for pay)? 
NO 
 YES
(If NO, check 'NO' 
and skip to question 6)
The next questions refer to tie past seven days. not including today_
2) During the past seven days. how many hours did you miss from work because of problems 
 associated 
with your CRPS? Include hours you missed on sick days, times you went in late, left early, etc., because of
problems associated with CRPS. Do not include time you missed to participate in this study.
HOURS
3) During the past seven days. how many hours did you miss from work because of any other reason, such
as vacation, holidays, time off to participate in this study?
HOURS
4) Dunng the past seven days. how many hours did you actually work?
HOURS (if 'V', skip to question 6)
5) During the past seven days. how much did CRPS affect your productivity while you were working? Think
about days you were limited in the amount or kind of work you could do, days you accomplished less than you
would like, or days you could not do your work as carefully as usual. If CRPS affected your work only a little.
choose a low number. Choose a high number if CRPS affected your work a great deal.
Consider only how much CRPS affected
productivity while you were working.
CRPS 
 
 CRPS
had no effect on my 0 1 
2 3 4 5 6 7 8 9 10 
completely
work 
prevented me
from working
CIRCLE A NUMBER
8) During the past seven days. how much did CRPS affect your ability to do your regular daily activities. other
than work at a job? By regular activities, we mean the usual activities you do, such as work around the
house, shopping, childcare, exercising, studying, etc. Think about times you were limited in the amount or
kind of activities you could do and times you accomplished less than you would like. If CRPS affected your
activities only a little, choose a low number. Choose a high number if CRPS affected your activities a great
deal.
Consider only how much CRPS affected your ability
to do your regular daily activities, other than work at a job.
CRPS 
 
 CRPS
had no effect on my 0 1 
2 3 4 5 8 7 8 6 10 
completely
daily activities 
prevented me
from doing my
daily activities
CIRCLE A NUMBER
+wu c::ws 
- u'si


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 95 of 128
DMS version 5.0
17 Nov 2017
18.4
Signs and symptoms of CRPS
DMS version: 
 
ID: 
 
5.0
1226379
Site # 
/ Subject ID
Date (MM/DDIYY)
/ 
/
CRPS SEVERITY SCORE
DATABASE FORM
Visit 1 a or Visit 2 o
DIAGNOSIS: K CRPS-I K CRPS-Ill D Non-CRPS: 
ETIOLOGY: (I Crush [i Surgery 0 
Fracture 
I.1 Laceration 
iJ Other: 
DATE INJURY: 
I 
! 
DATE SX ONSET: 
i 
/ 
LOCATION: D L K R K UE K LE
Current Numeric pain Rating Scale (NRS) of affected side: 
10; 24 lit worst 
+10; 24hr best 
 /0
SYMPTOMS 
Comments:
Circle "Yes" or "No" 
for each as reported by patient over the past 48 hours:
YES NO Continuing, disproportionate pain'
YES NO Allodvnia, and/or Hyperalgesia2: specify: Ll Alb 0Hyper
YES NO Temperature asymmetry3 lives, specify: ] 
Cold 0 
Warm iii Labile
YES NO Color asymmetry4 If yes, specify: 0 
Red 0 
Blue 0 
Other
YES NO Sweating asyrmnetry5
YES NO Edema6
YES NO Dystrophic changes? Ifyes,. speci(v: 0 
Nails 0 
Hair 0 
Skin
YES NO Motor abnormalitiess ,IfYes. specify: 0Weak OTremor ❑Dystonia
U Decreased ROM 0 
Myoclonus
SIGNS (as observed by examiner this date). Note any detailed comments on back:
YES NO Hyperalgesia to single pinprick9
YES NO Allodynia10 If ves..specie to: K Light Touch 0 
Deep Joint Pressure L Vibration 
K Cold K Heat
YES NO Temperature asymmetry by palpation" If yes. specify: K Affected Side Cooler 0 
Affected Side Warmer
YES NO Color asymmetry" 
Ifyes. specie,: Affected side: K Red K Blue or Pale K Mottled D Scar
YES NO Asymmetric Edema 13 Notes:   _
YES NO Sweating asymmetry" Yves, specify: K Increased on Affected Side 
K Decreased on Affected Side
YES NO Dystrophic changes15 lives, specie: K Nails 
K Hair 
K Skin. Notes: 
YES NO Motor abnor malitie516 lives. specify: K Tremor K Dystonia K Decreased Active ROM
0. Weakness 
/5 (Rate 0-5 of most affected joint)
Version Date: 3/29/2011  
CRPS Severity Score


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 96 of 128
DMS version 5.0
17 Nov 2017
18.5
Health Economics Outcome Questionnaire (sample)
DMS version: 
 
ID: 
 
5.0
1226379
GRUNENTHAL
Health Economics Outcome Questionnaire
Booklet KF7013-03
Page 1
Subject No. I I 
I 
I 
I 
II IIII
Visit 2 
(Day 1) / 
Visit 9 
(Week 26) / 
Visit 11(Week 52)
Date of assessment
I LJ 
/I I 
I 
I 
I
DD 
MMM 
YYYY
H EALTHCARE UTILIZATION 
Hospitalization
1. During the past 26 weeks, were you admitted overnight to a hospital (for more than 24 hours)?
0 
Yes
K No [SKIP to 2] 
0 
Don't know
1.a. 
If Yes, how many times were you hospitalized in the past 26 weeks? ____(#)
1.b. For each hospitalization (during the past 26 weeks), please provide the diagnosis or reason for
hospitalization, number of nights, and admission date:
#
Major Diagnosis or Reason for Hospitalization
# 
of Nights
Admission Date
1
W/i
I 
I
I/I 
i
1 
i
I
DD
MMM
YYYY
2
I 
I 
I/I
I 
I
I/1 
i
i 
i
I
DD
MMM
YYYY
3
I__LJ / 
I
i 
i
i / 
1 
i
1 
i
1
DD
MMM
YYYY
4
W/1
i 
i
1/1 
i
i 
i
I
DD
MMM
YYYY
5
W/i
I 
I
I/1 
i
1 
1
I
DD
MMM
YYYY
6
W/i
I 
I
I/1 
i
i 
i
I
DD
MMM
YYYY
7
I 
I 
I / 
I
I 
I
I / 
1 
i
1 
i
I
DD
MMM
YYYY
Note: Keep the original completed form in the subject file. Transcribe the data to the eCRF. Assure
consistency of the data related to reported medical history and adverse events for the subject.


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 97 of 128
DMS version 5.0
17 Nov 2017
DMS version: 
 
ID: 
 
5.0
1226379
GRUNENTHAL
Health Economics Outcome Questionnaire
Booklet KF7013-03
Page 2
Subject No. I 11111111 I 
I
Emergency Room (ER) Visit
2. During the past 26 weeks, did you receive care in an emergency room without being admitted to the
hospital?
K Yes
K No [SKIP to 3] 
K Don't know
2.a. 
If Yes, how many times in the past 26 weeks?
(#)
2.b. Please list the reason and date for each emergency room visit:
#
Major Reason for ER Visit
Date
1
W/i 
i
i
i/1 
i 
i 
i
1
DD
MMM YYYY
2
W/ 
i 
1
1
1/I 
i 
i 
i
I
OD
MMM YYYY
3
i
i
i/ i 
i
i i/mil
DD
MMM YYYY
Nursing Home (NH) Stay
3. During the past 26 weeks, did you spend any nights in a nursing home for any reason (physical or
emotional)?
K Yes
K No [SKIP to 4] 
0 
Don't know
3.a. 
If Yes, how many times in the past 26 weeks?
(#)
3.b. Please list reason, number of nights, and admission date for each nursing home stay:
#
Major Diagnosis or Reason for NH Stay
# 
of Nights
Admission Date
1
I
I
1/
/ 
I 
J 
i 
i 
I
DD
MMM YYYY
2
i
i
i/I
I 
I
i/1 
I 
I 
i 
l
DD
MMM YYYY
3
1
I
I/
/Imp
DD
MMM YYYY
Note: Keep the original completed form in the subject file. Transcribe the data to the eCRF. Assure
consistency of the data related to reported medical history and adverse events for the subject.


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 98 of 128
DMS version 5.0
17 Nov 2017
DMS version: 
 
ID: 
 
5.0
1226379
GRUNENTHAL
Health Economics Outcome Questionnaire
Booklet KF7013-03
Page 3
Subject No. I 1 
1 
1 
1 
1 1 1 
1 
1 
1
Outpatient Health Care Provider Contact
4. Which of the following types of health providers have you seen or had a telephone call with in the past 26
weeks on an outpatient basis? Indicate the provider frequency, major diagnosis or reason for visit, and
whether care was provided for CRPS-related pain or its symptoms. Please be careful not to double-count
services.
#
Provider Type
Used?
# 
visits in
past 26
weeks
# phone
calls in
past 26
weeks
Major Diagnosis or Reason for
Visit/Call
a
Family Medicine,
Internist, Primary
Care provider
K yes
K No
0 
Don't know
b
Pain specialist
K yes
K No
K Don't know
c
Psychiatrist
K yes
K No
K Don't know
d
Psychologist
K yes
K No
D 
Don't know
e
Neurologist
K yes
K No
K Don't know
f
Physician Assistant /
Nurse Practitioner
K yes
K No
D 
Don't know
g
Dentist
K yes
K No
D 
Don't know
h
Podiatrist
K yes
K No
K Don't know
Note: Keep the original completed form in the subject file. Transcribe the data to the eCRF. Assure
consistency of the data related to reported medical history and adverse events for the subject.


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 99 of 128
DMS version 5.0
17 Nov 2017
DMS version: 
 
ID: 
 
5.0
1226379
GRUNENTHAL
Health Economics Outcome Questionnaire
Booklet KF7013-03
Page 4
Subject No. I 1 
1 
1 
1 
1 1 1 
1 
1 
1
#
Provider Type
Used?
# 
visits in
past 26
weeks
# phone
calls in
past 26
weeks
Major Diagnosis or Reason for
Visit/Call
i
Integrated medicine
K yes
K No
K Don't know
j
Chiropractor
K yes
K No
K Don't know
k
Physical therapist
K yes
K No
K Don't know
I
Occupational
therapist
K yes
K No
K Don't know
m
Visiting nurse
K yes
K No
K Don't know
n
Home health aide
K yes
K No
K Don't know
o
Other specialty
(specify):
K yes
K No
K Don't know
p
Other specialty
(specify):
K yes
K No
K Don't know
q
Other specialty
(specify):
K yes
K No
K Don't know
Note: Keep the original completed form in the subject file. Transcribe the data to the eCRF. Assure
consistency of the data related to reported medical history and adverse events for the subject.


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 100 of 128
DMS version 5.0
17 Nov 2017
DMS version: 
 
ID: 
 
5.0
1226379
GRUNENTHAL
Health Economics Outcome Questionnaire
Booklet KF7013-03
Page 5
Subject No. I 1 
1 
1 
1 
1 1 1 
1 11
HOME SERVICES, HOME HELP, FORMAL AND INFORMAL CAREGIVING, 
DEVICES 
Home Services and Help
1. Which of the following types of services or help have you used in the past 26 weeks due to your CRPS-
related pain?
#
Program/Service Type
Used?
# times in past
26 weeks
Average duration
per time (min)
a
Cleaning or homemaking services
0 
Yes
K No
ICI Don't know
b
Meals delivered
K Yes
K No
K Don't know
c
Formal childcare / babysitting
assistance
K Yes
0 
No
❑Don't know
d
Transportation to help complete
daily errands (e.g., shopping, bank,
work, medical visits, pharmacy)
K Yes
0 
No
K Don't know
e
Formal and informal caregiving
K Yes
K No
K Don't know
Special Product / Device /Tool
2. Did you use any special equipment/assistive tools the past 26 weeks due to your CRPS-related pain?
Special
product / device
/ tool
Used?
#
Name of device/product/tool
f. Special
equipment
/assistive tools
K Yes
K No
K Don't know
1
2
3
4
5
6
Note: Keep the original completed form in the subject file. Transcribe the data to the eCRF. Assure
consistency of the data related to reported medical history and adverse events for the subject.


Grünenthal
Confidential
Protocol KF7013-03
including Amendment 04
Page 101 of 128
DMS version 5.0
17 Nov 2017
19
PROTOCOL AMENDMENTS
19.1
Protocol amendment 01
Amendment rationale
This amendment is implemented to:
•
Remove the requirement for blood sampling for a population pharmacokinetic analysis. A 
population pharmacokinetic analyses of the cumulative dose of 400 mg is not required 
because sufficient data have been collected in the trial KF7013-01.
•
To follow-up all subjects for up to 52 weeks.
•
To add continuous real-time ECG monitoring covering the period of infusions.
•
To modify the allowance of medications known to prolong the QT interval.
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: 
Title page
Trial sites: Multi-site trial (approximately 70 sites in the 
United States, Canada, and European Union)
Trial sites: Multi-site trial (approximately 70 sites in the 
United States and European Union)
Section 1.1.2: Brief description of the sequence and duration of all trial periods
Other data to be collected that is not directly attributed to 
an endpoint
Other data to be collected that is not directly attributed to 
or considered as an endpoint
Section 1.1.1: Flow diagram summary of the trial
The first 100 subjects will be followed through Week 52; 
subsequent subjects will be followed through Week 26
[Deleted]
Section 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, 
a treatment period consisting of 4 infusions over 10 days, 
and a follow-up period of approximately 50 weeks 
(Visit 6 [Week 2] through Visit 11 [Week 52]). After the 
first 100 subjects have been allocated to treatment, 
remaining subjects will have a shortened follow-up 
period of approximately 24 weeks (Visit 6 through 
Visit 9 [Week 26]). The first 100 subjects are expected to 
be in the trial for approximately 60 weeks (14 months).
The remaining subjects are expected to be in the trial for 
approximately 32 weeks (8 months). See Section 1.1.1 
for a summary of the trial as a flow diagram and 
Section 1.7 for a tabular schedule of events.
There will be an enrollment period lasting up to 60 days, 
a treatment period consisting of 4 infusions over 10 days, 
and a follow-up period of approximately 50 weeks 
(Visit 6 [Week 2] through Visit 11 [Week 52]). The 
subjects are expected to be in the trial for approximately 
60 weeks (14 months). See Section 1.1.1 for a summary 
of the trial as a flow diagram and Section 1.6 for a 
tabular schedule of events.
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Section 1.2: Trial objectives, endpoints, and outcomes
To assess the pharmacokinetics of neridronic acid in 
subjects with CRPS
Volume of distribution and clearance of neridronic acid 
in plasma, based on population pharmacokinetics 
modeling.
[Deleted]
Section 1.3.2: Exclusion criteria
1. Evidence of renal impairment (estimated glomerular 
filtration rate [eGFR] <60 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 creatinine ratio >30 mg/g), 
based on central safety laboratory data, or a history of 
chronic kidney disease.
...
3. Vitamin D deficiency, defined as a 25(OH)D level 
<30 ng/mL, based on central safety laboratory data 
obtained prior to Visit 2. Subjects with vitamin D 
deficiency should receive appropriate supplementation 
during the enrollment period. A normal vitamin D level 
(≥30 ng/mL) must be documented prior to allocation to 
investigational medicinal product (IMP).
...
[New exclusion criteria]
...
1. Evidence of renal impairment (estimated glomerular 
filtration rate [eGFR] <60 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 creatinine ratio >30 mg/g), 
based on central safety laboratory data, or a history of 
chronic kidney disease.
Note: If 2 consecutive laboratory tests indicate eGFR 
levels 60 mL/min/1.73 m2 or a single repeat laboratory 
test of the urinary albumin creatinine ratio is <30 mg/g 
during the enrollment period, the subject is eligible.
...
3. Vitamin D deficiency, defined as a 25(OH)D level 
<30 ng/mL, based on central safety laboratory data 
obtained prior to Visit 2 (a single repeat laboratory test 
is allowed). Subjects with vitamin D deficiency should 
receive appropriate supplementation during the 
enrollment period. A normal vitamin D level 
(≥30 ng/mL) must be documented prior to allocation to 
investigational medicinal product (IMP).
...
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, escotalopram) or 
tricyclic antidepressants 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 
until at least 4 days after the last infusion of IMP.
...
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Section 1.4.3: Prior/concomitant medications or therapies
The following medications and therapies are forbidden 
for the duration of the trial:
...
• High-dose opioid analgesics (>200 mg morphine 
equivalent daily dose) or combinations of opioids and 
benzodiazepines, as these regimens may have potential 
for significant opioid/sedatives side-effects that may be 
considered unstable or unsafe.
• Drugs with known risk of torsades de pointes. 
• Nerve blocks, radiofrequency ablation or other 
sympathectomy procedures, hyperbaric oxygen 
treatments, ketamine infusions, intravenous 
immunoglobulin, or other experimental therapies.
• Investigational drugs.
The following medications and therapies are forbidden 
for the duration of the trial:
...
• High-dose opioid analgesics (>200 mg morphine 
equivalent daily dose) or combinations of opioids and 
benzodiazepines, as these regimens may have potential 
for significant opioid/sedatives side-effects that may be 
considered unstable or unsafe.
• Nerve blocks, radiofrequency ablation or other 
sympathectomy procedures, hyperbaric oxygen 
treatments, ketamine infusions, intravenous 
immunoglobulin, or other experimental therapies.
• Investigational drugs.
The following medications and therapies are forbidden 
from 7 days prior to allocation until 4 days after the last 
infusion:
• Drugs with a known risk of torsades de pointes, 
excluding selective serotonin re-uptake inhibitor 
antidepressants (e.g., citalopram, escitalopram) and 
tricyclic antidepressants if QT interval values met entry 
criteria, subjects were on a stable dose for at least 1 
month prior to enrollment, and doses are expected to 
stay stable throughout the trial. 
Section 1.5.2: Subject populations
Pharmacokinetic Set:
All subjects with at least 1 evaluable pharmacokinetic 
concentration.
[Deleted]
Section 1.5.3: Statistical methods and analysis
Subject disposition will be summarized descriptively for 
all enrolled subjects. Discontinuations will be 
summarized descriptively for all allocated subjects. 
Demographic data, baseline characteristics, medical 
history, concomitant medications, and exposure will be 
summarized descriptively for the Safety Set. 
Pharmacokinetic and Pharmacodynamic parameters will 
be summarized descriptively for the Pharmacokinetic Set
and the Pharmacodynamic Set, respectively.
Subject disposition will be summarized descriptively for 
all enrolled subjects. Discontinuations will be 
summarized descriptively for all allocated subjects. 
Demographic data, baseline characteristics, medical 
history, concomitant medications, and exposure will be 
summarized descriptively for the Safety Set. 
Pharmacodynamic parameters will be summarized 
descriptively for the Pharmacodynamic Set.
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Section 1.5.3: Statistical methods and analysis: Secondary safety endpoints  and other safety data
Section 14.1.6.1: Adverse events
The incidences and incidence rates of all adverse events 
will be summarized descriptively. 
The distribution of time to onset of any TEAE will be 
summarized using time-to event methods. A graphical 
display using Kaplan-Meier methods displaying subjects 
at risk per time point will also be produced.
The incidences and incidence rates of all adverse events 
will be summarized descriptively. 
Permanent discontinuations from treatment due to 
adverse events will be summarized descriptively.
The distribution of time to onset of any TEAE will be 
summarized using time-to event methods. A graphical 
display using Kaplan-Meier methods displaying subjects 
at risk per time point will also be produced.
Section 1.6: Pharmacometric analyses
A previously developed population pharmacokinetics 
model will be updated using the plasma concentration 
data collected in this trial.
Exploratory evaluations of potential exposure-response 
relationships between neridronic acid exposure levels 
and selected safety markers (i.e., serum creatinine, 
eGFR, urinary albumin creatinine ratio, and QT interval 
assessments) as well as efficacy outcomes and 
pharmacodynamics markers (bone turnover markers, 
imaging markers) will be performed, if deemed 
appropriate.
Population pharmacokinetics and pharmacokinetics-
pharmacodynamics modeling will be performed by 
means of a nonlinear mixed effect modeling approach as 
implemented in NONMEM® Version 7. Other 
approaches will be applied, if deemed necessary.
[Section deleted]
Section 1.6: Schedule of events
Take blood for pharmacokinetic evaluation q
[Added to Day 1, Day 4, Day 7 and Day 10]
Perform continuous real-time ECG monitoring
[Deleted row]
Section 1.6: Schedule of events: Footnotes
c) This will be the final visit for all subjects allocated to 
treatment after the first 100 subjects allocated.
o) The diagnosis of CRPS must be confirmed according 
to the clinical diagnostic criteria recommended by the 
IASP (Budapest clinical criteria). The number of signs 
and symptoms of CRPS at each visit will be summed for 
determination of the CRPS Severity Score.
q) For Visit 2 through Visit 5, 1 blood sample for 
pharmacokinetic evaluation should be taken between 
[Deleted]
o) The diagnosis of CRPS must be confirmed using the 
tablet computer at Visit 1 according to the clinical 
diagnostic criteria recommended by the IASP (Budapest 
clinical criteria) (Section 12.2.3.1). The number of signs 
and symptoms of CRPS at Visit 2, and Visit 7 to Visit 11, 
inclusive, will be summed for determination of the CRPS 
Severity Score (Section 12.4.8).
[Deleted]
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5 minutes and 10 minutes prior to the start of the 
infusion and 1 blood sample from 45 minutes to 
5 minutes prior to the end of the infusion.
For Visit 2 and Visit 5, an additional sample should be 
taken between 5 minutes and 60 minutes after the end of 
the infusion.
For Visit 6, a single blood sample should be taken 
during the visit following all non-invasive procedures.
Blood samples for pharmacokinetic evaluation should 
be taken from a limb different to that used for the 
infusion and must not be taken from the infusion line.
...
s) For women of child-bearing potential, a negative urine 
pregnancy test result must be obtained prior to each 
infusion. Pregnancy testing should also be performed at 
Visit 11 for the first 100 subjects allocated or at Visit 9 
for subjects allocated to treatment after the first 100 
subjects have been allocated. For subjects who 
discontinue the trial prior to completion, pregnancy 
testing should be performed at the Early Termination 
Visit (whose procedures are identical to Visit 11).
t) The subject card is to be returned at the final visit or at 
the Early Termination Visit in the case of early 
discontinuation from the trial. After the first 100 subjects 
are allocated, the final visit for all subsequent subjects 
will be Visit 9 (Week 26).
...
s) For women of child-bearing potential, a negative urine 
pregnancy test result must be obtained prior to each 
infusion. For subjects who discontinue the trial prior to 
completion, pregnancy testing should be performed at 
the Early Termination Visit (whose procedures are 
identical to Visit 11).
t) The subject card is to be returned at the final visit or at 
the Early Termination Visit in the case of early 
discontinuation from the trial. 
Section 8.1: Discussion of the trial design
...
Normal bone mineralization and bone formation were 
observed in biopsies from regions of non-pagetic bone 
(iliac crest), and improved indices of bone turnover were 
observed in regions of pagetic bone. It is anticipated that 
15 evaluable biopsy specimens will be adequate to 
confirm normal bone mineralization in the iliac crest at 
approximately 6 months following treatment with 
neridronic acid 400 mg. Biopsies will be obtained from 
approximately 20 subjects to obtain 15 evaluable biopsy 
specimens. Biopsies will be obtained from 
approximately 20 subjects to obtain 15 evaluable biopsy 
specimens.
...
Normal bone mineralization and bone formation were 
observed in biopsies from regions of non-pagetic bone 
(iliac crest), and improved indices of bone turnover were 
observed in regions of pagetic bone. Biopsies will be 
obtained from approximately 20 subjects to obtain 15 
evaluable biopsy specimens. It is anticipated that 15 
evaluable biopsy specimens will be adequate to confirm 
normal bone mineralization in the iliac crest at 
approximately 6 months following treatment with 
neridronic acid 400 mg. Biopsies will be obtained from 
approximately 20 subjects to obtain 15 evaluable biopsy 
specimens. A 6 month time point was selected for the 
biopsy in order to match the slow kinetics of bone matrix 
and mineral apposition in humans, with approximately 6 
months required to complete a single remodeling cycle
(Riggs and Parfitt 2005).
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Section 8.2: Benefit/risk analysis: Risks  related to bone biopsies
Bone biopsies are performed as a minor outpatient 
surgery and are safe and generally well-tolerated (Kann 
et al. 2006, Hernandez et al. 2008). Risks include 
bleeding, hematoma, infection, superficial nerve injury, 
and pain. Most subjects experience soreness over the 
biopsy area for 4 days to 5 days. Subjects with increased 
risk of bleeding (e.g., hemostasis disorders, concomitant 
treatment with antithrombotic drugs) will be excluded 
from the bone biopsy assessments.
Bone biopsies are performed as a minor outpatient 
surgery and are safe and generally well-tolerated (Kann 
et al. 2006, Hernandez et al. 2008). Risks include 
bleeding, hematoma, infection, superficial nerve injury, 
and pain. Most subjects experience soreness over the 
biopsy area for 4 days to 5 days. Subjects with increased 
risk of bleeding (e.g., hemostasis disorders, concomitant 
treatment with antithrombotic drugs) will be excluded 
from the bone biopsy assessments.
It is unknown whether a bone biopsy could trigger or 
worsen CRPS in patients. The limited trials in which 
bone biopsies were performed in patients with CRPS or 
similar painful conditions have not suggested that this 
procedure would be likely to cause severe complications 
or worsening of CRPS, even when performed in a CRPS-
affected region. Since biopsies will be performed only in 
a region free of CRPS-related signs and symptoms, this 
is likely to mitigate the risk of worsening of the 
condition.
Section 9.3.1: Subject discontinuation from the trial
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.
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 
X
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.
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 
X
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or exclusion criteria and 
did not receive IMP)
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
Adverse event (e.g., 
subject experiences a 
significant deterioration 
in health such that 
further participation in 
the trial may jeopardize 
their ability to obtain 
other treatment)
X
Major protocol 
deviation (e.g., serious 
non-compliance with 
protocol procedures, 
unsafe use of forbidden 
medications, 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
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 
X
did not receive IMP).
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
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objective participation in 
the trial)
Section 9.3.2: Subject discontinuation from the IMP
Discontinuation of IMP applies only to the treatment 
period. Subjects who are discontinued from IMP should 
be encouraged to remain in the trial for follow-up 
assessments for their own safety and for the integrity of 
the trial.
The investigator may decide to temporarily suspend a 
subject from the IMP at any point during the treatment 
period if further assessment may be helpful to assure 
safety of the subject. In situations where treatment is 
temporarily discontinued (e.g., due to a potential safety 
concern or scheduling issue), and a decision is made (in 
consultation with the sponsor or sponsor’s designee) to 
resume treatment, the treatment period can be extended 
up to 21 days (i.e., Visit 5 should occur no later than 
21 days after Visit 2). A minimum period of 48 hours is 
required between infusions.
Investigators may 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 evidence of 
dehydration or deterioration in the subject’s health for 
reasons related or unrelated to the treatment. 
A subject must be discontinued from treatment if any of 
the following events occur during the treatment period:
• Symptomatic hypocalcemia.
• A persistent change in renal function, based on the 
following criteria:
− A 25% decrease from baseline in eGFR, 
relative to the last value obtained prior to 
treatment, observed on repeated serum 
creatinine measurements from the central 
safety laboratory at least one week apart. 
Subjects with any single 25% decrease in 
eGFR must be temporarily suspended 
from treatment and reassessed; if the 
repeated measurement of eGFR is within 
80% or more of the baseline value, the 
subject may resume treatment.
− Evidence of albuminuria based on a 
quantitative (central safety laboratory) 
urinary albumin creatinine ratio of 
>300 mg/g. The subject may resume 
treatment if the finding is confirmed to be 
<30 mg/g based on 2 consecutive urine 
Discontinuation of IMP applies only to the treatment 
period. Subjects who are discontinued from IMP should 
not be discontinued from the trial except for the 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 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, the treatment period may be extended to a 
maximum of 21 days (i.e., Visit 5 should occur no later 
than 21 days after Visit 2). Visit 6 will be scheduled to 
occur 4 days (±2 days) after Visit 5, but all subsequent 
visits should occur as originally scheduled relative to 
Visit 2 (e.g., Visit 7 will be 42 days [6 weeks] after 
Visit 2). No more than 4 infusions may be administered 
during the treatment period, and a minimum of 48 hours 
between any 2 infusions is required.
Table 2: Reasons for permanent and temporary 
discontinuation of subjects from IMP 
Discontinuation from 
IMP
Reason
Permanent
Temporary
Symptomatic 
hypocalcemia.
X
Serum calcium 
X
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samples, more than 1 day apart, analyzed 
at the central safety laboratory.
− An eGFR <50 mL/min/1.73m2 and urinary 
albumin creatinine ratio >150 mg/g.
• An average QTcF interval of >500 ms, or average 
QTcF interval of >480 ms with a concurrent 
increase in average QTcF interval >60 ms from 
enrollment (average of 3 ECGs).
• Pregnancy.
• Development of hypersensitivity to the IMP.
Central safety laboratory data from the previous visit, in 
particular eGFR, must be evaluated prior to each 
infusion.
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 3 days may 
resume treatment. Subjects with persistent signs and 
symptoms of ocular inflammation must be discontinued 
from IMP and undergo an ophthalmologic examination.
<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.
Clinical signs of 
dehydration (e.g., 
dizziness, palpitations, 
confusion).
X
Evidence suggestive of a 
possible change in renal 
function:
• A persistent 25% 
decrease from baseline 
(last value observed 
prior to treatment) in the 
eGFR, based on 
repeated central 
laboratory results from 
blood samples obtained 
at least 1 week apart a.
X
• A 25% decrease from 
baseline in the eGFR. If 
a repeated measurement 
of eGFR is within 75% 
or more of the baseline 
value, the subject may 
resume treatment a.
X
• A persistent urinary 
ACR >300 mg/g based 
on quantitative urinary 
albumin and creatinine 
data from the central 
laboratory, with 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 
X
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creatinine data from the 
central laboratory 
indicate a urinary ACR 
value <30 mg/g.
• A persistent eGFR 
<50 mL/min/1.73m2 and
urinary ACR >150 mg/g 
based on repeated 
quantitative data from 
the central laboratory, 
with blood and urine 
samples obtained at 
least 1 week apart.
X
• An eGFR 
<50 mL/min/1.73m2 and
urinary ACR >150 mg/g 
based on results of the 
central laboratory or 
semiquantitative urinary 
dipstick.
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
• Resolution of signs and 
symptoms within 5 days.
X
• Persistent signs and 
symptoms.
X
At any point during the 
treatment period if 
further assessment may 
be helpful to assure 
safety of the subject.
X
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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 prohibited 
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) Baseline values of eGFR are obtained from central 
laboratory results after Visit 2 (based on the blood 
sample taken at Visit 2 prior to the first administration of 
IMP). Evaluation of change from baseline in eGFR must 
occur prior to Visit 4 and Visit 5, based on assessment of 
central laboratory results from blood samples taken 
prior to Visit 3 and Visit 4, respectively.
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 signs and 
symptoms of ocular inflammation must be discontinued 
from IMP and undergo an ophthalmologic examination.
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Section 10.1.2: Preparation
The volume of IMP transferred to the infusion bag must 
be recorded and the transfer procedure must be witnessed 
by a second individual who documents confirmation of 
the transferred volume.
The volume of IMP transferred to the infusion bag must 
be recorded.
Section 10.2: Administration of investigational medicinal product
The full contents of a single ampule or 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 neridronic acid 400 mg. The 
complete solution volume of 500 mL should be 
administered at each infusion visit unless treatment is 
suspended for safety reasons.
The full contents of a single ampule or 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 neridronic acid 400 mg. The 
complete solution volume of 500 ± 50 mL should be 
administered at each infusion visit unless treatment is 
suspended for safety reasons.
Section 11.1: Course of the trial
All visits should be attended in a fasting state (at least 
8 hours).
All visits should be attended in a fasting state (at least 
8 hours). A non-fasting state does not constitute a 
protocol deviation.
Section 11.1.1.1: Visit 1 (Day -60 to Day -1)
• Complete the assessment of the signs and symptoms of 
CRPS (for further details, see Section 12.2.3.1).
• The diagnosis of CRPS must be confirmed  using the 
tablet computer at Visit 1 according to the clinical 
diagnostic criteria recommended by the IASP (Budapest 
clinical criteria) (for further details, see 
Section 12.2.3.1).
Section 11.1.2.1: Visit 2 (Day 1)
Section 11.1.2.2: Visit 3 (Day 4; ±1 day)
Section 11.1.2.3: Visit 4 (Day 7; ±1 day)
Section 11.1.2.4: Visit 5 (Day 10; ±1 day)
Record triplicate 12-lead ECG (once at least 15 minutes 
before the infusion and once at least 15 minutes after the 
infusion).
Record concomitant medications and therapies.
...
Collect urine for central safety laboratory urinalysis and 
local dipstick evaluation (calculate urinary albumin 
creatinine ratio).
Take blood for pharmacokinetic evaluation (before, 
during, and after infusion; see Section 1.7 for time 
points).
Record triplicate 12-lead ECG (once at least 15 minutes 
before the infusion and once at least 15 minutes after the 
infusion).
Perform continuous real-time ECG monitoring (for 
details, see Section 12.3.4).
Record concomitant medications and therapies.
...
Collect urine for central safety laboratory urinalysis and 
local dipstick evaluation (calculate urinary albumin 
creatinine ratio).
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Section 11.1.3.1: Visit 6 (Week 2; ±2 days)
Collect urine for central safety laboratory urinalysis.
Take blood for pharmacokinetic evaluation (see 
Section 1.7 for time point).
Collect urine for central safety laboratory urinalysis.
Section 11.1.3.4: Visit 9 (Week 26; ±15 days)
A single bone biopsy will be obtained from the iliac 
crest, following tetracycline double-labeling, in a subset 
of subjects (from US sites only). The biopsy should be 
scheduled to be performed 26 weeks after the first 
administration of IMP. Biopsies will be obtained from 
approximately 20 subjects to obtain 15 evaluable biopsy 
specimens.
This will be the final visit for all subjects allocated to 
treatment after the first 100 subjects allocated.
A single bone biopsy will be obtained from the iliac 
crest, following tetracycline double-labeling, in a subset 
of subjects (from US sites only). The biopsy should be 
scheduled to be performed 26 weeks after the first 
administration of IMP. Biopsies will be obtained from 
approximately 20 subjects to obtain 15 evaluable biopsy 
specimens.
Section 11.2: Examination hierarchy and time windows
Electrocardiograms 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.
Electrocardiograms should be taken before invasive 
procedures. When practical, blood samples for safety 
laboratory evaluation should be taken after all non-
invasive procedures (including completion of 
questionnaires) have been finished.
Section 12.1: Overview of blood sampling in this trial
The total blood volume drawn per subject will be 
approximately 250 mL during the trial (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).
The total blood volume drawn per subject will be 
approximately 200 mL during the trial (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).
Section 12.1: Overview of blood sampling in this trial: Table 2
Pharmacokinetic evaluation a  4 mL  11  44 mL
Total (US sites) 51    217.5 mL
Total (EU sites) 62    245 mL
[Row deleted]
Total (US sites) 40    173.5 mL
Total (EU sites) 51    201 mL
Section 12.1: Overview of blood sampling in this trial: Table 2: Footnotes
a) Population pharmacokinetics will be analyzed on an 
ongoing basis throughout the trial.
b) Includes vitamin D testing.
a) Includes vitamin D testing.
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Section 12.2.3.1: Diagnosis of CRPS
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.
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 active range of motion, or 
weakness) (see Section 18.4).
Section 12.3.4: Continuous real-time ECG monitoring
[New Section]
Continuous real-time ECG monitoring, which may be 
performed by telemetry, will be performed at the infusion 
visits (Day 1, Day 4, Day 7, and Day 10), starting at 
least 30 minutes prior to the beginning of each infusion 
and for up to at least 30 minutes after the end of each 
infusion. Continuous real-time ECG monitoring must be 
performed by a qualified person. Personnel trained in 
advanced cardiopulmonary resuscitation must be on site 
and readily available to treat any potential cardiac 
rhythm disturbances.
Electrocardiogram machines may be used for continuous 
real-time ECG monitoring.
Section 12.3.5: Safety laboratory: Hematology panel
White blood cell (WBC) count with differential count if 
abnormal
White blood cell (WBC) count with differential count 
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Section 12.3.8: Bone biopsy procedures
An iliac crest biopsy will be obtained 5 days to 14 days 
after the last dose of tetracycline according to procedures 
of Dempster and Shane (1995). 
Biopsies will be performed using a Bordier type biopsy 
needle with a minimum internal diameter of 7.5 mm to 
ensure an adequate sample size. Evaluable biopsies must 
contain inner and outer cortical plates with intervening 
cancellous bone. The biopsy will be performed only by 
investigators who are skilled and experienced in this 
procedure. For subjects with lower limb CRPS, the 
biopsy must be taken from the hip contralateral to the 
CRPS-affected limb. 
An iliac crest biopsy will be obtained 5 days to 14 days 
after the last dose of tetracycline according to procedures 
of Dempster and Shane (1995). Prior to the bone biopsy, 
subjects may receive optional intravenous sedation. The 
site of the biopsy will be numbed with a local anesthetic 
(e.g., xylocaine, lidocaine) to minimize discomfort.
Biopsies will be performed using a Bordier type biopsy 
needle with a minimum internal diameter of 7.5 mm to 
ensure an adequate sample size. Evaluable biopsies must 
contain inner and outer cortical plates with intervening 
cancellous bone. The biopsy will be performed only by 
investigators who are skilled and experienced in this 
procedure. For subjects with lower limb CRPS, the 
biopsy must be taken from the hip contralateral to the 
CRPS-affected limb. 
Subjects will return to the bone biopsy center 7 days to 
10 days after the bone biopsy to have stitches removed.
Section 12.2.4.2: Urine drugs of abuse test
Subjects who are receiving benzodiazepines for medical 
purposes or opioids or opioid-containing medications
may participate even if the test for benzodiazepine or 
opioids is positive.
Subjects who are receiving stable doses of prescribed 
medications containing amphetamines, benzodiazepines, 
or opioids may participate even if the test is positive.
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Section 12.5: Collection of plasma concentration data
Blood sampling for bioanalysis
Details of the blood sample collection times are given in 
the schedule of events (Section 1.7).
The exact sampling time must be recorded in the CRF.
The blood samples 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 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 for further bioanalytical analysis 
if deemed necessary.
The bioanalytical report (PK1729A), including a 
description of the assay and a summary of the assay 
performance data, will be included in the final integrated 
clinical trial report.
[Sections deleted]
Section 14.1.8: Analysis of neridronic acid plasma concentration data
Neridronic acid plasma concentrations at the respective 
time points will be summarized using descriptive 
statistics and optionally graphs for the Pharmacokinetic 
Set.
[Section deleted]
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Section 14.2: Pharmacometric analyses
The population pharmacokinetics and population 
pharmacokinetics-pharmacodynamics modeling and 
simulation in this trial will be planned and performed by 
sponsor personnel or by authorized sponsor delegates.
A previously developed population pharmacokinetics 
model will be updated using the plasma concentration 
data collected in this trial.
Exploratory evaluations of potential exposure-response 
relationships between neridronic acid exposure levels 
and selected safety markers (i.e., serum creatinine, 
eGFR, urinary albumin creatinine ratio, QT interval 
assessments) as well as efficacy outcomes and 
pharmacodynamics markers (bone turnover markers, 
imaging markers) will be performed, if deemed 
appropriate.
Population pharmacokinetics and population 
pharmacokinetics-pharmacodynamics modeling will be 
performed by means of a nonlinear mixed effect 
modeling approach as implemented in NONMEM®
Version 7. Other approaches will be applied, if deemed 
necessary.
The results of this analysis will be reported in a 
pharmacometric report, i.e., separately from the 
integrated clinical trial report.
[Section deleted]
Section 14.1.12: Ad hoc meta-analyses
Data collected in this trial may be used for ad hoc meta-
analyses, e.g., to explore 
pharmacokinetic/pharmacodynamic relationships. These 
meta-analyses will be planned, performed, and reported 
by sponsor personnel or by authorized sponsor delegates 
in accordance with sponsor SOPs.
Data collected in this trial may be used for ad hoc meta-
analyses. These meta-analyses will be planned, 
performed, and reported by sponsor personnel or by 
authorized sponsor delegates in accordance with sponsor 
SOPs.
Section 16.6: Trial results reporting
A final report integrating clinical, pharmacokinetic, 
pharmacodynamics and statistical results will be 
prepared by the sponsor. The international coordinating 
investigator will approve the final report on behalf of the 
participating investigators.
A final report integrating clinical, pharmacodynamics 
and statistical results will be prepared by the sponsor. 
The international coordinating investigator will approve 
the final report on behalf of the participating 
investigators.
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Section 17: References: Publications
Al Nofal AA, Altayar O, BenKhadra K, Qasim Agha OQ,
Asi N, Nabhan M, et al. Bone turnover markers in 
Paget's disease of the bone: A Systematic review and 
meta-analysis. Osteoporos Int. 2015; 26(7):1875-91.
...
Jung K, Lein, M. Bone turnover markers in serum and 
urine as diagnostic, prognostic and monitoring 
biomarkers of bone metastasis. Biochim Biophys Acta 
2014; 1846:425-438.
...
Naylor K, Eastell R. Bone turnover markers: use in 
osteoporosis. Nat Rev Rheumatol 2012; 8(7): 379-89.
...
Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: 
the critical need for a uniform nomenclature based on 
their action on bone remodeling. J Bone Miner Res 
2005; 20 (2): 177-84.
Section 18.3.7: Work Productivity and Activity Impairment Questionnaire: CRPS
CPRS had no effect on daily activities
CPRS had no effect on my daily activities
19.2
Protocol amendment 02
Amendment rationale
This amendment is implemented to:
•
Exclude subjects who are taking forbidden concomitant medications/therapies or are not 
able to follow the rules for use of concomitant medications/treatments.
•
Revise the dose rationale to include additional information from a previous pilot study.
•
State that treatment discontinuation will be permanent if eye symptoms reoccur.
•
Clarify the distribution of ampules and vials during the trial.
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 1.3.2: Exclusion criteria
18. Subject is engaged in litigation related to their 
disability from CRPS in which monetary gain or loss (or 
18. Subject is engaged in litigation related to their 
disability from CRPS in which monetary gain or loss (or 
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other compensation) may affect their objective 
participation in the trial.
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 1.4.3).
Section 1.4.1: Investigational medicinal product
The first batch of IMP is supplied in glass ampules, each 
containing 108 mg sodium neridronate hemi hydrate 
(equivalent to 100 mg neridronic acid) in a total volume 
of 8 mL. Subsequent batches of IMP will be supplied in 
vials.  
The first batch of IMP will be provided to sites in the US
in glass ampules, each containing 108 mg sodium 
neridronate hemi hydrate (equivalent to 100 mg 
neridronic acid) in a total volume of 8 mL. Subsequent 
batches of IMP will be supplied in vials.
Sites in the EU will receive all batches of IMP in glass 
vials.
Section 8.1.1: Rationale for the investigational medicinal product and the selected dose
A placebo-controlled trial in 82 subjects with CRPS-I 
indicated that 400 mg of neridronic acid, administered as 
four 2-hour infusions of 100 mg in 10 days, is safe, well-
tolerated and effective for treatment of pain and other 
symptoms of CRPS (Varenna et al. 2013).
A placebo-controlled trial in 82 subjects with CRPS-I 
indicated that 400 mg of neridronic acid, administered as 
four 2-hour infusions of 100 mg in 10 days, is safe, well-
tolerated and effective for treatment of pain and other 
symptoms of CRPS (Varenna et al. 2013).
A pilot trial of neridronic acid involving cumulative 
intravenous doses of 200 mg, 300 mg, and 400 mg 
neridronic acid in patients with CRPS-I suggested that 
the 400 mg cumulative dose was optimally effective. As 
the 4 x 100 mg dose regimen 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 neridronic 
acid 100 mg to treat Paget’s disease of bone, 
osteogenesis imperfecta, and CRPS-I is 2 hours. To limit 
the maximum concentrations (Cmax) in this trial to levels 
similar to those obtained in the KF7013-01 trial, in 
which neridronic acid 62.5 mg was infused in 2 hours, 
the infusion time has been extended to 4 hours.
Alternative dosage forms or routes of administration for 
neridronic acid are limited to an intramuscular dosage 
form (25 mg per ampule, available in Italy), which would 
be impractical for administering a 400 mg total dose. An 
oral dosage form is not available and would have 
practical limitations due to the very low bioavailability 
of bisphosphonates (typically reported in the range of 
1%).
Section 9.3.2: Subject discontinuation from the IMP
Table 2: Reasons for permanent and temporary 
discontinuation of subjects from IMP
[…]
• Persistent signs and symptoms.
Table 2: Reasons for permanent and temporary 
discontinuation of subjects from IMP
[…]
• Persistent or recurrent signs and symptoms
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[…]
[…]
Subjects with resolution of signs and symptoms within 
5 days may resume treatment. Subjects with persistent 
signs and symptoms of ocular inflammation must be 
discontinued from IMP and undergo an ophthalmologic 
examination.
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.
Section 10.1.2: Preparation
The first batch of IMP will be provided in glass ampules 
and must be removed using a filter needle (to remove 
any possible glass particles). Instructions will be 
provided for proper handling of ampules and filter 
needles. Subsequent batches of IMP will be supplied in 
vials, which do not require the use of filter needles. 
Instructions will be provided for the proper handling of 
vials.
The first batch of IMP will be provided to sites in the US
in glass ampules and must be removed using a filter 
needle (to remove any possible glass particles). 
Instructions will be provided for proper handling of 
ampules and filter needles. Subsequent batches of IMP 
will be supplied in vials, which do not require the use of 
filter needles. Instructions will be provided for the proper 
handling of vials. 
Sites in the EU will receive all batches of IMP in glass 
vials.
Section 10.1.3: Packaging and labelling
The IMP will be supplied in kits consisting of 4 ampules 
or 4 vials of IMP.
The IMP will be supplied in kits consisting of either
4 ampules (initially for US sites) or 4 vials (US and EU 
sites) of IMP.
19.3
Protocol amendment 03
Amendment rationale
This amendment is implemented to:
•
Apply all changes introduced in protocol amendment 02 (valid for Germany) to all 
countries.
•
Clarify that Visit 1 does not need to be performed in a fasted state.
•
Adjust the duration of stable contraceptive use from 2 months to 1 month prior to 
allocation.
•
Allow repeat testing of eGFR, ACR, serum calcium or magnesium, and vitamin D level.
•
Clarify that the combination of opioids and benzodiazepines is forbidden only if the 
combination is felt to jeopardize subject safety, in the opinion of the investigator.
•
Introduce re-enrollment of suitably qualified subjects who failed allocation due to technical 
reasons.
•
Clarify that the drugs of abuse testing is performed at the site and that the investigator 
should judge whether subjects who are receiving stable doses of prescribed medications 
containing amphetamines, benzodiazepines, or opioids can participate (together with 
approval by the sponsor).
•
Exclude subjects who are incapable of signing the informed consent.
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•
Only include subjects who have failed at least 2 available treatments for CRPS, 1 of which 
must be a pharmacologic treatment.
•
Adjust the exclusion criterion for urinary ACR from <30 mg/g to <150 mg/g, due to impact 
on enrollment of subjects with moderate levels of urinary albumin and based on lack of 
evidence for changes in urinary ACR in the KF7013-01 trial.
•
Adjustment of the temporary IMP discontinuation criteria to allow resumption of treatment 
if the urinary ACR is <150 mg/g, and removal of the temporary discontinuation criterion 
for eGFR <50 mL/min/1.73 m2 and urinary ACR >150 mg/g.  A persistent change of this 
magnitude remains as a criterion for permanent discontinuation.
•
Adapt the time period for collection of dental history.
•
Clarify that the definition of the pharmacodynamics set includes only subjects who have 
been treated.
•
Clarify requirements for documentation of abnormal laboratory values. Only values that are 
outside of the sponsor-defined alert ranges require documentation in the CRF. Laboratory 
values that are outside of the laboratory reference ranges do not require documentation in 
the CRF.
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 1.3.1: Inclusion criteria
5. In stable treatment and follow-up therapy for CRPS 
for at least 1 month prior to allocation to treatment 
(Visit 2).
[…]
6. Women of child-bearing potential must have a 
negative urine beta-human chorionic gonadotropin (β-
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 <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 2 months prior to 
Visit 2 and for the duration of the trial.
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 trials of at least 
2 treatments for CRPS, one of which must be a 
pharmacologic treatment (see Section 1.4.3).
[…]
6. Women of child-bearing potential must have a 
negative urine beta-human chorionic gonadotropin (β-
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 <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.
Section 1.3.2: Exclusion criteria
1. Evidence of renal impairment (estimated glomerular 
1. Evidence of renal impairment (estimated glomerular 
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filtration rate [eGFR] <60 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 creatinine ratio >30 mg/g), 
based on central safety laboratory data, or a history of 
chronic kidney disease. 
Note: If 2 consecutive laboratory tests indicate eGFR 
levels 60 mL/min/1.73 m2 or a single repeat laboratory 
test of the urinary albumin creatinine ratio is <30 mg/g 
during the enrollment period, the subject is eligible.
[…]
filtration rate [eGFR] <60 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 creatinine ratio [ACR]
>150 mg/g), based on central safety laboratory data
obtained prior to Visit 2, or a history of chronic kidney 
disease. 
Note: a single repeat laboratory test is allowed.
[…]
3. Vitamin D deficiency, defined as a 25(OH)D level 
<30 ng/mL, based on central safety laboratory data 
obtained prior to Visit 2 (a single repeat laboratory test is
allowed). Subjects with vitamin D deficiency should 
receive appropriate supplementation during the 
enrollment period. A normal vitamin D level 
(≥30 ng/mL) must be documented prior to allocation to 
investigational medicinal product (IMP).
[…]
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.
[…]
19. Subjects taking forbidden concomitant 
medications/therapies or not being able to follow the 
rules of use of concomitant treatment (see Section 1.4.3).
3. Vitamin D deficiency, defined as a 25(OH)D level 
<30 ng/mL, 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 must be documented prior to allocation to 
investigational medicinal product (IMP).
[…]
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 2.
[…]
19. Subjects taking forbidden concomitant 
medications/therapies or not being able to follow the 
rules of use of concomitant treatment (see Section 1.4.3).
20. Subjects incapable of signing the informed consent.
Section 1.4.3: Prior/concomitant medications or therapies
Subjects enrolled in the trial are encouraged to continue 
standard of care…
[…]
The following medications and therapies are forbidden 
for the duration of the trial:
• Drugs with the potential to cause hypocalcemia (e.g., 
aminoglycosides). Subjects on a stable dose of 
furosemide or other loop diuretics may continue
treatment as long as no dosage changes are anticipated 
and calcium levels remain in the reference range.
• Oral or intravenous bisphosphonates, calcitonin, 
denosumab, or other bone-active drugs (e.g., 
teriparatide).
• High-dose opioid analgesics (>200 mg morphine 
equivalent daily dose) or combinations of opioids and 
Enrolled subjects must have failed trials of at least 
2 treatments for CRPS, 1 of which must be a 
pharmacologic treatment. A failed trial is defined by 
continuing pain. Such treatments may be prior to or 
continuing at enrollment and can include any analgesic 
medication (including non-steroidal anti-inflammatory 
drugs [NSAIDs], opioids, antidepressants, etc.), 
interventional therapy (e.g., nerve block or spinal cord 
stimulation), or physical therapy.
Subjects are encouraged to continue standard of care…
[…]
The following are forbidden as concomitant medications 
and therapies during the trial:
• Drugs with the potential to cause hypocalcemia (e.g., 
aminoglycosides). Subjects on a stable dose of 
furosemide or other loop diuretics may receive treatment 
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benzodiazepines, as these regimens may have potential 
for significant opioid/sedatives side-effects that may be 
considered unstable or unsafe.
[…]
• Drugs with a known risk of torsades de pointes, 
excluding selective serotonin re-uptake inhibitor 
antidepressants (e.g., citalopram, escitalopram) and 
tricyclic antidepressants if QT interval values met entry 
criteria, subjects were on a stable dose for at least 
1 month prior to enrollment, and doses are expected to 
stay stable throughout the trial. 
with IMP as long as no dosage changes in the diuretic 
medications are anticipated and calcium levels are in the 
reference ranges.
• Oral or intravenous bisphosphonates, calcitonin, 
denosumab, or other bone-active drugs (e.g., 
teriparatide).
• High-dose opioid analgesics (>200 mg morphine 
equivalent daily dose) or combinations of opioids and 
benzodiazepines or any other treatment regimen 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).
[…]
• Drugs with a known risk of torsades de pointes, 
excluding selective serotonin re-uptake inhibitor 
antidepressants (e.g., citalopram, escitalopram) and 
tricyclic antidepressants if QT interval values met entry 
criteria, subjects were on a stable dose for at least 
1 month prior to allocation, and doses are expected to 
stay stable throughout the trial.
Section 1.5.2: Subject populations
Pharmacodynamic Set: All subjects with at least 1 non-
missing value for at least 1 of the bone turnover markers.
Pharmacodynamic Set: All treated subjects with at 
least 1 non-missing value for at least 1 of the bone 
turnover markers.
Section 1.6: Schedule of events
Collect urine for drugs of abuse testing
[…]
All visits should be attended in a fasting state (at least 
8 hours).
[…]
e) Dental history will include: date of last dental visit; 
dental extractions and other invasive dental surgery in 
past 12 months;
Perform urine drugs of abuse testing
[…]
All visits, except Visit 1, should be attended in a fasting 
state (at least 8 hours).
[…]
e) Dental history will include: date of last dental visit; 
dental extractions and other invasive dental surgery in 
past 3 months prior to the Enrollment Visit;
Section 8.2: Benefit/risk analysis
Hypocalcemia
[…]
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.
All subjects will be provided with supplemental calcium 
and vitamin D, starting from Visit 1 and continuing 
through to the end of the trial. Recommended doses are 
Hypocalcemia
[…]
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 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 
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500 mg to 1000 mg per day elemental calcium and 
approximately 1000 IU/day vitamin D. A combination 
product of calcium and vitamin D may be used. Subjects 
with vitamin D deficiency (<30 ng/mL) at enrollment 
may receive higher doses of vitamin D during the 
enrollment period (e.g., 10 000 IU/day for 10 days) to 
raise vitamin D levels to protocol required levels. 
Vitamin D will be reduced to approximately 1000 IU/day 
prior to starting treatment at Visit 2. Investigators should 
promote compliance by instructing the subject to take the 
supplements as prescribed and by stating that compliance 
is important for subject safety. 
[…]
and vitamin D, starting from Visit 1 and continuing 
through to the end of the trial. Recommended doses are 
500 mg to 1000 mg per day elemental calcium and 
approximately 1000 IU/day vitamin D. A combination 
product of calcium and vitamin D may be used. Subjects 
with vitamin D levels below 30 ng/mL at enrollment 
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. Vitamin D 
will be reduced to approximately 1000 IU/day prior to 
the start of treatment at Visit 2. Repeat laboratory testing 
for vitamin D is permitted during the enrollment period 
(up to a maximum of 4 times in 60 days). Investigators 
should promote compliance by instructing the subject to 
take the supplements as prescribed and by stating that 
compliance is important for subject safety.
[…]
Pregnancy and breastfeeding
There is no clinical experience with pregnant or lactating 
subjects treated with neridronic acid. 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.
[…]
Conclusion
As there are currently no Food and Drug Administration 
(FDA) approved treatments for serious chronic pain 
conditions with unmet medical needs and there is limited 
clinical evidence for benefit of available pain 
medications, the potential for benefit of neridronic acid 
is considered to outweigh the potential risk. The need for 
controlled safety as well as efficacy trials of potential 
new treatments for CRPS justifies this trial on moral and 
ethical grounds.
Pregnancy and breastfeeding
There are no adequate and well-controlled trials of 
neridronic acid in pregnant or lactating women. 
Although there are no data to suggest a 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.
[…]
Conclusion
As there are currently no Food and Drug Administration 
(FDA) approved 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 safety as well as efficacy trials of 
potential new treatments for CRPS justifies this trial on 
moral and ethical grounds.
Section 9.1: 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.
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 CRPS treatment; inadequate time from 
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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.
Section 9.3.2: Subject discontinuation from the IMP
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.
[…]
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).
[…]
• 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 
<30 mg/g.
• 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.
• A persistent eGFR <50 mL/min/1.73m2 and urinary 
ACR >150 mg/g based on repeated quantitative data 
from the central laboratory, with blood and urine 
samples obtained at least 1 week apart.
• An eGFR <50 mL/min/1.73m2 and urinary ACR 
>150 mg/g based on results of the central laboratory or 
semiquantitative urinary dipstick.
• A persistent eGFR <50 mL/min/1.73 m2 and urinary 
ACR >150 mg/g based on repeated quantitative data 
from the central laboratory, with blood and urine 
samples obtained at least 1 week apart.
Section 10.1.2: Preparation
The volume of IMP transferred to the infusion bag must 
be recorded.
The volume of IMP transferred to the infusion bag must 
be recorded in the CRF.
Section 11.1: Course of the trial
All visits should be attended in a fasting state (at least 
8 hours).
All visits, except Visit 1, should be attended in a fasting 
state (at least 8 hours).
Section 11.1.1.1: Visit 1 (Day -60 to Day -1)
• Collect urine for drugs of abuse testing.
• Perform urine drugs of abuse testing.
Section 12.1: Overview of blood sampling in this trial
The total blood volume drawn per subject will be 
approximately 200 mL during the trial…
[…]
Table 3: Planned approximate blood sampling volumes 
collected from each subject
The total blood volume drawn per subject is estimated to
be less than 180 mL during the trial…
[…]
Table 3: Planned approximate blood sampling volumes 
collected from each subject
[…]
[…]
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Serum bicarbonate (EU 
sites only)
(2.5 mL)
(11)
(27.5 mL)
Total (US sites)
40
173.5 mL
Total
40
173.5 mL
Total (EU sites)
51
201 mL
Section 12.2.3.2: Dental history
Dental history will include the date of last dental visit; 
dental extractions and other invasive dental surgery in 
past 12 months…
Dental history will include the date of last dental visit; 
dental extractions and other invasive dental surgery in 
past 3 months prior to the Enrollment Visit…
Section 12.2.4.2: Urine drugs of abuse test
Urine samples will be provided by the subject at the 
Enrollment Visit for testing for drugs of abuse . The 
drugs to be screened for using suitable validated methods 
(e.g., dipstick) include:
[…]
Urine samples will be provided by the subject at the 
Enrollment Visit 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 CRF:
[…]
Subjects who are receiving stable doses of prescribed 
medications containing amphetamines, benzodiazepines, 
or opioids may participate even if the test is positive.
Subjects who are receiving stable doses of prescribed 
medications containing amphetamines, benzodiazepines, 
or opioids may participate (according to the judgment of 
the investigator upon approval by the sponsor) even if 
the test is positive.
Section 12.3.5: Safety laboratory
Laboratory tests (except for urine dipstick) will be 
performed by a central safety laboratory.
[…]
Throughout the clinical part of the trial, the investigator 
must provide feedback regarding the clinical relevance of 
any laboratory values outside the reference range.
Laboratory tests (except for urine dipsticks for urine 
drugs of abuse testing and urine pregnancy testing) will 
be performed by a central safety laboratory.
[…]
Throughout the clinical part of the trial, the investigator 
must provide a comment in the CRF regarding the 
clinical relevance of any laboratory values outside of the 
sponsor-defined alert range.
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19.4
Protocol amendment 04
Amendment rationale
This amendment is implemented to:
•
Increase the size of the target population.
•
Clarify the planned number of bone biopsies and bone densitometry and MRI assessments.
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 1.5.1: Sample size rationale
The sample size is intended to maximize available safety 
data to support product registration. In combination with 
subjects receiving active treatment in the ongoing 
placebo-controlled trial (KF7013-01) and further planned 
trials of neridronic acid, the number of subjects included 
in this trial is intended to support regulatory 
requirements for at least 500 subjects evaluated for 
safety. It is estimated that approximately 220 subjects 
will be included in this trial; the actual number of 
subjects allocated, however, may depend on enrollment 
in ongoing and further planned trials.
The sample size is intended to maximize available safety 
data in line with the FDA regulatory requirements to 
support product registration. It is estimated that 
approximately 290 subjects will be included in this trial.
Section 1.6: Schedule of events
u) Bone densitometry (DXA) and MRI will be performed
in a subset of 30 subjects .
v) A single bone biopsy will be obtained from the iliac 
crest, following tetracycline double-labeling, in a subset 
of subjects. The biopsy should be scheduled to be 
performed 26 weeks after the first administration of IMP. 
Biopsies will be obtained from approximately 
20 subjects  to obtain 15 evaluable biopsy specimens .
u) It is planned to perform bone densitometry (DXA) 
and MRI in a subset of 30 subjects.
v) A single bone biopsy will be obtained from the iliac 
crest, following tetracycline double-labeling, in a subset 
of subjects. The biopsy should be scheduled to be 
performed 26 weeks after the first administration of IMP. 
It is planned to obtain approximately 15 evaluable bone 
biopsy samples from approximately 20 subjects.
Section 8.1: Discussion of the trial design
Normal bone mineralization and bone formation were 
observed in biopsies from regions of non-pagetic bone 
(iliac crest), and improved indices of bone turnover were 
observed in regions of pagetic bone. Biopsies will be 
obtained from approximately 20 subjects to obtain 
15 evaluable biopsy specimens. It is anticipated that 
15 evaluable biopsy specimens will be adequate to
confirm normal bone mineralization in the iliac crest at 
approximately 6 months following treatment with 
neridronic acid 400 mg. A 6 month time point was 
selected for the biopsy in order to match the slow 
kinetics of bone matrix and mineral apposition in 
Normal bone mineralization and bone formation were 
observed in biopsies from regions of non-pagetic bone 
(iliac crest), and improved indices of bone turnover were 
observed in regions of pagetic bone. It is planned to 
obtain approximately 15 evaluable bone biopsy 
specimens from approximately 20 subjects. It is 
anticipated that bone biopsy specimen evaluation will 
confirm normal bone mineralization in the iliac crest at 
approximately 6 months following treatment with 
neridronic acid 400 mg. A 6 month time point was 
selected for the biopsy in order to match the slow 
kinetics of bone matrix and mineral apposition in 
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humans, with approximately 6 months required to 
complete a single remodeling cycle (Riggs and Parfitt 
2005).
A subset of 30 subjects will undergo bone densitometry 
and MRI to assess the effect of neridronic acid on 
BMD…
humans, with approximately 6 months required to 
complete a single remodeling cycle (Riggs and Parfitt 
2005).
It is anticipated that a subset of 30 subjects will undergo 
bone densitometry and MRI to assess the effect of 
neridronic acid on BMD…
Section 11.1.1.1: Visit 1 (Day -60 to Day -1)
• Perform bone imaging (DXA and MRI will be 
performed in a subset of 30 subjects [from US sites 
only]).
• Perform bone imaging (DXA and MRI will be 
performed in a subset of approximately 30 subjects [from 
US sites only]).
Section 11.1.3.4: Visit 9 (Week 26; ±15 days)
A single bone biopsy will be obtained from the iliac 
crest, following tetracycline double-labeling, in a subset 
of subjects (from US sites only). The biopsy should be 
scheduled to be performed 26 weeks after the first 
administration of IMP. Biopsies will be obtained from 
approximately 20 subjects to obtain 15 evaluable biopsy 
specimens.
[…]
• Perform bone imaging (DXA and MRI will be 
performed in a subset of 30 subjects [from US sites 
only]).
A single bone biopsy will be obtained from the iliac 
crest, following tetracycline double-labeling, in a subset 
of subjects (from US sites only). The biopsy should be 
scheduled to be performed 26 weeks after the first 
administration of IMP. Biopsies will be obtained from 
approximately 20 subjects to obtain approximately 
15 evaluable biopsy specimens.
[…]
• Perform bone imaging (DXA and MRI will be 
performed in a subset of approximately 30 subjects [from 
US sites only]).
Section 14.1.1: Sample size rationale
Subset of subjects for bone biopsies
The sample size is not based on statistical considerations; 
15 evaluable biopsy specimens are considered adequate 
to be able to identify qualitative bone abnormalities such 
as osteomalacia as well as quantitative indicators of 
impaired mineralization.
Subset of subjects for bone densitometry and 
magnetic resonance imaging
The sample size is not selected based on statistical 
considerations. Results from 30 subjects are considered 
to be sufficient to demonstrate feasibility and support a 
rationale for the future use of these assessments in trials 
of neridronic acid in CRPS.
Subset of subjects for bone biopsies
The sample size is not based on statistical considerations; 
bone biopsy specimen evaluation will identify qualitative 
bone abnormalities such as osteomalacia as well as 
quantitative indicators of impaired mineralization.
Subset of subjects for bone densitometry and 
magnetic resonance imaging
The sample size is not selected based on statistical 
considerations. Results from this subset of subjects are 
considered to be sufficient to demonstrate feasibility and 
explore outcomes of these assessments in trials of 
neridronic acid in CRPS.
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0
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kf7013-03-sap
Functional Expert Approval
16-May-2018 11:06 GMT+0
Biostatistics Approval
16-May-2018 11:12 GMT+0
Clinical Approval
16-May-2018 23:11 GMT+0


Confidential
Page 1 of 50
SDR-SAP-TRIAL-06
CONFIDENTIAL
No part of this document may be passed on, reproduced or published without written 
permission of Grünenthal
STATISTICAL ANALYSIS PLAN
Trial number:
KF7013-03
Title of trial:
Open-label safety trial of intravenous neridronic acid in subjects 
with complex regional pain syndrome (CRPS)
EudraCT number:
2016-001164-11
Universal Trial Number:
U1111-1180-8099
Development phase:
Phase III
Investigational medicinal 
product:
Intravenous neridronic acid
Version
Date
DMS version number
Final Version
Amendment 01
12 Dec 2016
15 May 2018
1.0
2.0
This document was approved according to the sponsor’s standard operating procedures.
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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS
2
LIST OF TABLES
4
LIST OF FIGURES
5
2
ABBREVIATIONS
6
3
INTRODUCTION
7
4
TRIAL OBJECTIVES
7
5
TRIAL DESIGN
8
5.1
Overall trial design and plan
8
5.2
Sample size
8
5.3
Randomization
9
6
OVERVIEW OF PLANNED ANALYSES
9
6.1
Final analysis
9
6.2
Interim analyses
9
7
DOCUMENT AND CHANGE HISTORY
9
7.1
Changes in analysis compared to the trial protocol
9
7.2
Rationale for changes from pre-final to final SAP
9
7.3
SAP amendment rationale
10
8
ANALYSIS CONVENTIONS
11
8.1
General principles
11
8.2
Definitions
13
8.2.1
Definition of subgroups
13
8.2.2
Further definitions
14
9
SUBJECT POPULATIONS
15
9.1
Enrolled Set
15
9.2
Allocated Set
15
9.3
Safety Set
15
9.4
Full Analysis Set
15
9.5
Treatment Completers Set
15
9.6
Pharmacodynamic Set
15
9.7
Bone Biopsy Set
16
9.8
Bone Imaging Set
16
10
DISPOSITION
16
10.1
Subject disposition
16
10.2
Subject discontinuations
17
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10.3
Protocol deviations
17
11
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
18
11.1
Subject demographics
18
11.2
Other baseline characteristics
18
11.3
Subject medical history
18
11.3.1
Medical history
18
11.3.2
Dental history
19
11.3.3
Complex regional pain syndrome history
19
11.4
Prior and concomitant medication or therapy
19
12
EXPOSURE AND COMPLIANCE
19
12.1
Exposure
19
12.2
Compliance
20
13
EFFICACY ANALYSES
20
13.1
Primary endpoint
20
13.2
Secondary endpoints
20
13.2.1
Main analysis
21
13.2.2
Sensitivity analysis
23
13.2.3
Other analysis
23
13.3
Analysis of other efficacy data
23
13.3.1
Average and worst pain intensity
23
13.3.2
Pain Disability Index score
24
13.3.3
EuroQoL-5 dimension 5 level score and VAS
24
13.3.4
Pain Anxiety Symptom Scale
24
13.3.5
Center for Epidemiological Studies Depression Scale score
25
13.3.6
Complex Regional Pain Syndrome Severity Score
25
14
ANALYSIS OF PHARMACOKINETIC AND 
PHARMACODYNAMICS PARAMETERS
28
14.1
Analysis of pharmacokinetic data
28
14.2
Analysis of pharmacodynamic data
28
14.2.1
Bone turnover markers
28
14.2.2
Bone densitometry and magnetic resonance imaging procedures
28
15
SAFETY ANALYSES
29
15.1
Adverse events
29
15.1.1
Incidence, incidence rates and number of events
30
15.2
Laboratory parameters, vital signs, and ECG parameters
32
15.2.1
Laboratory parameters
33
15.2.2
Vital signs
36
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15.2.3
Electrocardiogram
36
15.3
Physical examination
37
15.4
Bone biopsy procedures
37
15.5
Primary endpoint
37
15.6
Secondary safety endpoint
38
16
HEALTH ECONOMICS OUTCOME AND WORK PRODUCTIVITY 
DATA
38
16.1
Work Productivity and Activity Impairment Questionnaire: CRPS
38
16.2
Medical resources utilization and health economics data
38
17
INTERIM ANALYSIS
39
17.1
Interim analysis of efficacy
39
17.2
Interim analysis of safety
39
18
REFERENCES
39
19
CHANGES TO THE SAP
40
19.1
Changes from pre-final to final version
40
19.2
Amendments
40
20
APPENDIX
40
20.1
Data derivation and analysis rules
40
20.1.1
General specifications
40
20.1.2
Disposition
42
20.1.3
Demographics and other baseline characteristics
42
20.1.4
Efficacy analysis
44
20.1.5
Analysis of pharmacokinetic and pharmacodynamic parameters
44
20.1.6
Safety analysis
44
20.2
List of statistical output documentation
49
20.3
Reference ranges and alert ranges
49
20.3.1
Reference ranges for vital signs
49
20.3.2
Sponsor-defined alert ranges for vital signs
49
20.3.3
Sponsor-defined alert ranges for ECG parameters
50
LIST OF TABLES
Table 1:
Use of analysis sets
13
Table 2: 
Assessments of CRPS signs and symptoms
26
Table 3:
Analysis of laboratory parameters
34
Table 4:
Analysis of vital signs parameters
36
Table 5:
Analysis of ECG parameters
37
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Table 6:
Presentation of descriptive statistics in clinical trials
40
Table 7: 
Reference ranges for vital sign parameters
49
Table 8: 
Sponsor-defined alert ranges for vital sign parameters
50
Table 9: 
Sponsor-defined alert ranges for ECG parameters
50
LIST OF FIGURES
Figure 1:
Flow diagram summary of the trial
8
Figure 2:
Graphical overview about the imputation strategy
45
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2
ABBREVIATIONS
Abbreviation
Explanation
ACR
Albumin creatinine ratio
ADaM 
Analysis Data Model 
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BAP
Bone alkaline phosphatase
ß-HCG
ß-human chorionic gonadotropin
BMI
Body mass index
BPI
Brief Pain Inventory
CES-D
Center for Epidemiological Studies Depression Scale
CI
Confidence interval
CIR
Crude incidence rate
CRPS
Complex regional pain syndrome
CTX
C-terminal telopeptide of type I collagen
DMC
Data monitoring committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EQ VAS
EuroQol visual analog scale
EQ-5D-5L
EuroQol 5-dimension 5-level questionnaire
EU
European Union
FAS
Full Analysis Set
ICTR
Integrated clinical trial report
ID
Identification
IMP
Investigational medicinal product
IRT
Interactive response technology
LSmeans
Least square means
MDMA
3,4-methylendioxy methamphetamine, ecstasy
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MMRM
Mixed effects model for repeated measures
MNAR
Missing-not-at-random
MRI
Magnetic resonance imaging
N, n
Number of subjects
nMiss
Number of missing values
NRS
Numerical rating scale
PASS
Pain Anxiety Symptom Scale
PDI
Pain Disability Index
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Abbreviation
Explanation
PD Set
Pharmacodynamic Set
PGIC
Patient Global Impression of Change
PPS
Per Protocol Set
PINP
Procollagen type I amino-terminal propeptide
PT
Preferred Term
Q1
First quartile 
Q3
Third quartile
QTcB
Corrected QT interval (according to Bazett’s formula)
QTcF
Corrected QT interval (according to Fridericia’s formula)
SAF
Safety Set
SAP
Statistical analysis plan
SAS
Statistical analysis software®
SD
Standard deviation
SI
Système International d’Unités
SOC
System Organ Class
SDTM
Study Data Tabulation Model
TCS
Treatment Completers Set
TEAE
Treatment emergent adverse event
ULN
Upper limit of normal
USA
United States of America
VAS
Visual analog scale
WHO-DD
World Health Organization Drug Dictionary
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 KF7013-03 in accordance with the protocol version 5.0 dated 17 Nov 2017, and the eCRF
DMS version 5.0 dated 28 Jul 2017. The analysis will be performed by a contract research 
organization in accordance with this SAP.
4
TRIAL OBJECTIVES
Primary objective:
•
To assess the safety and tolerability of neridronic acid in subjects with CRPS.
Secondary objectives:
•
To assess the safety and tolerability of neridronic acid in subjects with CRPS.
•
To assess the efficacy of neridronic acid in the treatment of CRPS.
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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, open-label, single-arm, Phase III safety trial of intravenous neridronic acid in 
subjects with CRPS.
There will be an enrollment period lasting up to 60 days, a treatment period consisting of 
4 infusions over 10 days, and a follow-up period of approximately 50 weeks (Visit 6 [Week 2] 
through Visit 11 [Week 52]). The subjects are expected to be in the trial for approximately 
60 weeks (14 months). See Figure 1 for a summary of the trial as a flow diagram. For details, refer 
to the schedule of events defined in the trial protocol.
Figure 1:
Flow diagram summary of the trial
The investigational medicinal product (IMP) is 100 mg neridronic acid 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.
In addition to the assessments applicable to all trial subjects, bone biopsies will be performed in a 
subset of trial subjects to assess the bone safety of neridronic acid 400 mg. In addition, bone 
imaging assessments (bone densitometry and magnetic resonance imaging) will be performed in a 
subset of trial subjects. Bone biopsies and bone imaging data will only be obtained from subjects 
participating at sites in the United States of America (USA).
An external independent data monitoring committee (DMC) will periodically review safety 
information from the trial and monitor trial conduct and overall progress.
5.2
Sample size
The sample size is intended to maximize available safety data to support product registration. In 
combination with subjects receiving active treatment in the ongoing placebo-controlled trial 
(KF7013-01) and further planned trials of neridronic acid, the number of subjects included in this 
trial is intended to support regulatory requirements for at least 500 subjects on neridronic acid 
evaluated for safety. It is estimated that approximately 290 subjects will be included in this trial.
For bone biopsies, results from 15 evaluable biopsy specimens are considered adequate to be able to 
identify qualitative bone abnormalities such as osteomalacia as well as quantitative indicators of 
impaired mineralization.
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Enrollment Period
Treatment Period
Follow-up Period
Visit 1  
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Day 1
Day 4
Day 7
Day 10
Week 2
Week 6
Week 12
Week 26
Week 39
Week 52
Nelldronic acid 100 mg win be administered
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For bone densitometry and magnetic resonance imaging (MRI) assessments, results from 
30 subjects are considered sufficient to demonstrate feasibility and support a rationale for the future 
use of these assessments in trials of neridronic acid in CRPS.
If the expected number of bone biopsies or bone densitometry and MRI assessments are not 
obtained, it is not planned to increase the number of subjects included in the trial.
5.3
Randomization 
Not applicable.
6
OVERVIEW OF PLANNED ANALYSES 
6.1
Final analysis
The final analysis will be performed after all subjects have completed the trial, and the data has 
been hard locked. The results of the final analysis will be the basis for the integrated clinical trial 
report.
6.2
Interim analyses
An external DMC will periodically review safety information from the trial and monitor trial 
conduct and overall progress. For details on the interim analysis, please refer to Section 17.
7
DOCUMENT AND CHANGE HISTORY
7.1
Changes in analysis compared to the trial protocol
This section summarizes the changes in the analysis compared to the protocol.
Protocol
SAP
Section 1.5.2
Section 9.4
Full Analysis Set: All subjects who are allocated and 
treated.
The Full Analysis Set includes all subjects allocated with 
at least 1 IMP administration, including any partial 
infusion.
Reason: To align with the definition of the SAF.
Section 14.1.3
Section 9.4
The Pharmacodynamic Set includes all subjects with at
least 1 non-missing value for at least 1 of the bone
turnover markers.
The Pharmacodynamic Set includes all treated subjects 
with at least 1 non-missing value for at least 1 of the 
bone turnover markers 
Reason: Only treated subjects were intended for 
inclusion in this analysis set.
7.2
Rationale for changes from pre-final to final SAP
Not applicable.
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7.3
SAP amendment rationale
The rationale for amendment 01 on the final SAP is to implement the changes resulting from the 
protocol amendments and project decisions . In addition, minor corrections and revisions were 
performed.
In the table below, deleted text is crossed out and new text is highlighted using italics.
Change from final
Rationale for change
Section 3
This statistical analysis plan (SAP) includes all definitions and analysis 
details for the analysis for DMC periodic meetings of the trial KF7013-03 in 
accordance with the protocol version 4.05.0 dated 19 Apr 17 Nov 2017, and 
the eCRF version 1.0 5.0 dated 17 Nov 2016 28 Jul 2017. The analysis will 
be performed by a contract research organization in accordance with this 
SAP.
Update to the latest version of 
protocol and eCRF. 
Section 5.1
The sample size is intended to maximize available safety data to support 
product registration. In combination with subjects receiving active treatment 
in the ongoing placebo-controlled trial (KF7013-01) and further planned 
trials of neridronic acid, the number of subjects included in this trial is 
intended to support regulatory requirements for at least 500 subjects 
evaluated for safety. It is estimated that approximately 220 290 subjects will 
be included in this trial; the actual number of subjects allocated, however, 
may depend on enrollment in ongoing and further planned trials.
According to Protocol Amendment 5, 
the sample size was increased. 
Section 8.2.1
Not applicable.
Two subgroups will be defined based on the duration of CRPS:
1. Subjects with duration ≤2 year from onset of symptoms suggestive of 
CRPS.
2. Subjects with duration >2 year from onset of symptoms suggestive of 
CRPS.
When subgroup analyses are specified, the analysis will be performed 
separately in each of the subgroups and overall.
To add subgroup analyses.
Section 10.2
Reasons for discontinuations from the trial and from IMP will be presented 
for:
•
Subjects allocated and discontinued from the trial 
•
Subjects allocated and discontinued IMP intake.
•
Subjects allocated and discontinued from the trial per trial phase, 
i.e., during the treatment period, and during the follow-up period
overall, and separately for the first 100 subjects (Visit 11) and for 
subsequent subjects (Visit 9).
According to Protocol Amendment 1 
from 21 Oct 2016, the design of the 
trial was changed, all subjects are 
treated and analyzed in the same way, 
no need for separate analyses. 
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Section 13.2
The following secondary efficacy endpoints will be analyzed overall and by 
subgroups:
Change from baseline to Week 12 and Week 26 in the current pain 
intensity score, using a numerical rating scale (NRS).
•
Response to treatment, defined as at least 30%, and at least 50% 
and at least 2 points on the NRS decrease from baseline in the 
current pain intensity score, at Week 12 and Week 26.
•
Patient Global Impression of Change (PGIC) at Week 12 and 
Week 26.
•
Change from baseline to Week 12 and Week 26 in the Pain 
Interference score of the Brief Pain Inventory (BPI).
To add subgroup analysis for 
secondary efficacy endpoints and add 
‘at least 2 points on the NRS ’ in the 
responder analyses
Section 13.2.1.2
Descriptive summaries of the responder status will be presented by visit for 
each of the 3 responder definition. This includes the summary of the 
secondary responder endpoints, i.e., the response to treatment defined as at 
least 30%, and at least 50% and at least 2 points on the NRS decrease from 
baseline at Week 12 (Visit 8) and Week 26 (Visit 9).
To add ‘at least 2 points on the NRS ’ 
in the responder analyses
Section 13.3
The following outcome parameters based on other efficacy data collected in 
this trial will be analyzed for the FAS:
To add analysis population for other 
efficacy data.
Section 15.2.1 
In table 3, mean plot and shift plot are added for parathyroid hormone, 
vitamin D and calcium. 
To align with the analyses for DMC
Section 20.1.1.14
If the last available visit is between Visit 2 and Visit 7, data from the early 
termination visit will be assigned to the next scheduled visit; otherwise 
Visit 9 or Visit 11 in the follow-up period. D data will be assigned to the 
nearest scheduled visit based on the trial day of the early termination visit 
and the planned visit day. The planned visit day is:
•
Day 182 for Visit 9 (Week 26).
•
Day 273 for Visit 10 (Week 39).
•
Day 365 for Visit 11 (Week 52).
To specify the imputation methods 
and programming instructions more 
clearly.  
Section 19.2
Not applicable.
Changes are made from Final SAP version 1.0 to SAP Amendment Version 
2.0, all the changes are documented in Section 7.3.
To document the changes in the 
versions of SAP. 
8
ANALYSIS CONVENTIONS
8.1
General principles
If 2 or more of the population sets as defined in the SAP coincide, presentations will only be 
prepared for 1 population.
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All presentations will be done overall, i.e., for the single treatment group neridronic acid 400 mg.
The data collected and derived in 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: 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 20.1.1.2.
•
Categorical variables: absolute and relative frequencies. If not defined otherwise, the 
percentage denominator will be the number of subjects still in the trial at the respective time
point in the analyzed population.
•
Time-to-event variables: number of subjects, number of subjects with event, number of 
censored subjects, first quartile, median, and third quartile including 95% confidence 
interval. For calculating the survival estimate confidence interval (CI) bounds, the log-log 
transformed estimate of CI bounds will be used. In addition, Kaplan-Meier estimates and 
plots will be provided with the respective number at risk and the Kaplan-Meier estimates at 
the relevant time points together with the median and its 95% CI. Censoring mechanisms 
will be described in the respective section.
Medical terms (e.g., prior and concomitant diseases, adverse events) will be coded via Medical 
Dictionary for Regulatory Activities (MedDRA), and 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
TCS
PD Set
Subject disposition
X
Discontinuations
X
Protocol deviations
X
Demographics
X
Other baseline characteristics
X
Subject medical history
X
Previous and concomitant 
medication
X
Exposure
X
Compliance
X
Primary safety endpoint
X
Secondary safety endpoint
X
Secondary efficacy endpoints
X
X
Adverse events
X
Laboratory values
X
Vital signs
X
Twelve-lead ECG
X
Physical examination
X
Bone turnover markers
X
Health economics data
X
ECG = electrocardiogram; FAS = Full Analysis Set; PD Set = Pharmacodynamic Set; SAF = Safety Set;
TCS = Treatment Completers Set.
8.2
Definitions
8.2.1
Definition of subgroups
Two subgroups will be defined based on the duration of CRPS:
1. Subjects with duration ≤2 year from onset of symptoms suggestive of CRPS.
2. Subjects with duration > year from onset of symptoms suggestive of CRPS.
When subgroup analyses are specified, the analysis will be performed separately in each of the 
subgroups and overall.
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8.2.2
Further definitions
Term
Definition
Baseline 
For this single-arm non-randomized trial, baseline is the last observation (scheduled or 
unscheduled) before first IMP administration, unless specified otherwise. In general, 
baseline is the value recorded at Visit 2.
For physical examinations, a general assessment will be done at Visit 1, and at all 
subsequent visits (scheduled or unscheduled) the change compared to the previous visit 
will be assessed. 
For bone imaging assessments, a separate baseline visit must be scheduled during the 
enrollment period for subjects undergoing bone densitometry and magnetic resonance 
imaging procedures.
Early termination visit
Subjects who discontinue the follow-up period before their last planned visit should 
undergo an Early Termination Visit with procedures identical to Visit 11. If a subject 
discontinues then, the data recorded under Visit 11 in the eCRF are treated as data 
belonging to the Early Termination Visit.
Follow-up period
The follow-up period starts after the treatment period and ends at Visit 11.
Follow-up completers
Subjects completing Visit 11 in the follow-up period. Intermittent missed visits in the 
follow-up period are allowed and do not affect the follow-up completion status.
Investigational Medicinal 
Products (IMP) 
Neridronic acid in the form of sodium neridronate hemi hydrate 108 mg for intravenous 
infusion (equivalent to 100 mg neridronic acid) supplied in 8 mL of excipients. The full 
contents of a single ampule or 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 neridronic acid 400 mg.
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 Visit 11 for trial completers, and otherwise at the
Early Termination Visit for discontinued subjects. This is based on the persistence in 
bone and potentially prolonged effect of neridronic acid.
Pooling of sites
Individual sites will be combined to achieve pooled sites of similar size and with a 
sufficient number of subjects. Sites will be pooled by geographical region. The majority 
of sites are located in the United States of America (USA). Sites in the USA will be 
pooled in 4 regions based on United States (US) states:
•
US North East: Connecticut (CT), Delaware (DE), Illinois (IL), Indiana (IN), 
Maine (ME), Maryland (MD), Massachusetts (MA), Michigan (MI), New 
Hampshire (NH), New Jersey (NJ), New York (NY), Ohio (OH), Pennsylvania 
(PA), Rhode Island (RI), Vermont (VT), and Washington D.C. (DC).
•
US South East: Alabama (AL), Florida (FL), Georgia (GA), Kentucky (KY), 
North Carolina (NC), South Carolina (SC), Tennessee (TN), Virginia (VA), and 
West Virginia (WV).
•
US Midwest: Arkansas (AR), Colorado (CO), Iowa (IA), Kansas (KS), Louisiana 
(LA), Minnesota (MN), Mississippi (MS), Missouri (MO), Montana (MT),  
Nebraska (NE), New Mexico (NM), North Dakota (ND), Oklahoma (OK), South 
Dakota (SD), Texas (TX), Wisconsin (WI), and Wyoming (WY).
•
US West: Alaska (AK), Arizona (AZ), California (CA), Hawaii (HI), Idaho (ID), 
Nevada (NV), Oregon (OR), Utah (UT), and Washington (WA).
The sites in Europe will be pooled in one region, European Union (EU).
Pre-treatment-period
Before first IMP administration (excluded), i.e., the period between signature of the 
informed consent form and first administration of IMP.
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Term
Definition
Subjects discontinued 
from treatment
Subjects permanently discontinued from IMP, i.e., subjects who stopped 
treatment prior to, or at any time during Visit 2, 3, 4, or 5.
Treated subjects
Subjects with at least 1 administration of IMP, including partial infusions.
Treatment period
The treatment period includes the four infusion visits starting at Visit 2 up to 
Visit 5. If a subject is permanently discontinued from treatment, the treatment 
period ends at the visit of the last infusion.
Treatment completers
Treated subjects who completed IMP administration according to the protocol, i.e., 
subjects who received the full dose of all 4 planned infusions of IMP. Treatment 
completers form the Treatment Completers Set defined below.
Trial completers
All subjects completing Visit 11 according to the protocol. 
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.
9.3
Safety Set
The Safety Set includes all subjects with at least 1 IMP administration, including any partial 
infusion. The Safety Set will be the primary analysis set in this trial.
Analysis on the SAF will be conducted on the actual treatment received. 
9.4
Full Analysis Set
The Full Analysis Set includes all subjects allocated with at least 1 IMP administration, including 
any partial infusion. In this trial, the Full Analysis Set coincides with the Safety Set.
Analysis on the FAS will be conducted according to the allocated treatment. In this single-arm trial,
the allocated treatment is the same as the actual treatment.
9.5
Treatment Completers Set
The Treatment Completers Set (TCS) includes all treated subjects who completed IMP 
administration according to the protocol, i.e., subjects who received the full dose of all 4 planned 
infusions of IMP.
9.6
Pharmacodynamic Set
The Pharmacodynamic Set (PD Set) includes all treated subjects with at least 1 non-missing value 
for at least 1 of the bone turnover markers will be included in the Pharmacodynamic Set.
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9.7
Bone Biopsy Set
All subjects with at least 1 bone biopsy evaluable for histology or histomorphometry will be 
included in the Bone Biopsy Set.
9.8
Bone Imaging Set
All subjects with at least 1 DXA or MRI image evaluable for BMD (DXA) or bone marrow lesion 
volume (MRI) will be included in the Bone Imaging Set.
10
DISPOSITION
10.1
Subject disposition
All presentations for subject disposition will be overall, i.e., for the single treatment group 
neridronic acid 400 mg.
For describing the subject disposition, the following populations will be summarized:
•
Subjects enrolled.
•
Subjects enrolled but not allocated and reason for non-allocation.
•
Subjects allocated.
•
Safety Set.
•
Full Analysis Set.
•
Treatment Completers Set (i.e., Treatment completers).
•
Pharmacodynamic Set.
•
Bone Biopsy Set.
•
Bone Imaging Set.
•
Trial completers.
•
Follow-up completers.
•
Subjects allocated and discontinued from the trial.
•
Subjects allocated and discontinued from the trial per trial phase, i.e., during the treatment 
period, and during the follow-up period.
•
Subjects who received 4 infusions, including partial infusions.
•
Subjects allocated and discontinued IMP intake.
•
Subjects allocated and discontinued IMP intake due to deterioration in renal function.
For subjects enrolled but not allocated and for the reasons for not being allocated, the percentage 
denominator will be the number of enrolled subjects. For all other calculations, the percentage 
denominator will be the number of allocated subjects.
In addition, an overview table will be prepared presenting the number of subjects enrolled, 
allocated, in the SAF, in the FAS, in the TCS, PD Set, Bone Biopsy Set, and Bone Imaging Set if 
applicable per country. Percentage calculation will be done in two ways: 
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•
The denominator will be the number of all allocated subjects.
•
The denominator will be the number of allocated subjects in the respective country.
Reasons for exclusion from the analysis populations will be summarized. The percentage 
denominator will be the number of subjects allocated.
10.2
Subject discontinuations
Discontinuations from the trial and from IMP will be presented for allocated subjects overall, and 
per country. 
Reasons for discontinuations from the trial and from IMP will be presented for:
•
Subjects allocated and discontinued from the trial 
•
Subjects allocated and discontinued IMP intake.
•
Subjects allocated and discontinued from the trial per trial phase, i.e., during the treatment 
period, and during the follow-up period
Percentage denominator will be the number of subjects discontinuing.
The details for “other reasons” will be presented in a listing, if applicable.
If more than 10% of the allocated subjects discontinue the trial/IMP the distribution of the time to 
discontinuation from trial/IMP will be summarized using time-to-event methods. Time will be days 
until discontinuation. The time to discontinuation from the trial will be censored at the subject’s last 
planned visit, i.e., Visit 11. The time to discontinuation from IMP will be censored at the last 
planned infusion visit (Visit 5) or at the early termination visit in case of premature discontinuation 
from the trial, whichever occurs first.
All data will be presented in a subject data listing sorted by site.
10.3
Protocol deviations
Major protocol deviations will be summarized overall, and by pooled site and site based on the SAF
and will be grouped into different categories such as:
Category code
Category definition
PD01
Violation of inclusion/ exclusion criteria
PD02
Time schedule deviations
PD03
Non-compliance regarding intake of IMP or rescue medication
PD04
Inappropriate intake of concomitant medication
PD05
Missing essential data
PD06
Subject not discontinued as per protocol
PD07
Other protocol deviations
NC08
Other GxP non-compliance
Major protocol deviations will be presented in a subject data listing sorted by treatment, pooled site, 
and site.
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The list of definitions of protocol deviations (SDN-NONCOMP-DEF-01) may be updated during 
the trial and will be finalized before database lock. Multiple deviations can occur in the same 
subject and thus a subject can be counted in more than 1 deviation category.
11
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Subject demographics and baseline characteristics will be summarized descriptively overall, i.e., for 
the single treatment group neridronic acid 400 mg, for the SAF.
This also applies to the summaries of medical history including dental history and CRPS history, 
and the summaries of prior and concomitant medication or therapy.
11.1
Subject demographics
Subject demographics are age [years], height [m], sex, race, ethnicity, and age group. Age group 
will be derived. Age groups will be <18 years, ≥18 years and <65 years, ≥65 years and <85 years,
and ≥85 years.
All demographic data will be presented in a subject data listing.
The continuous variables age and height will be descriptively summarized. Sex, race, ethnicity, and 
age group will be summarized as categorical variables.
Remark: Weight is recorded repeatedly together with the vital sign parameters. Therefore, weight 
and body mass index (BMI) are described in Section 15.2.2).
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 with assessments collected later on in the trial and not in a separate 
table. 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 electrocardiogram (ECG) parameters.
•
Vital signs parameters.
•
Bone turnover markers.
•
Health economics questionnaires (WPAI-CRPS, medical resource utilization).
Moreover, the analysis of the urine drugs of abuse test at the Enrollment Visit is described in 
Section 15.2.1.
11.3
Subject medical history
11.3.1
Medical history
All medical history data will be presented in a subject data listing.
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Medical history will be summarized and sorted alphabetically, separately for prior and concomitant 
diseases, by primary System Organ Class (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 analyzed separately in the same way as the medical history.
11.3.3
Complex regional pain syndrome history
All CRPS history data will be presented in a subject data listing.
The CRPS history will be descriptively summarized. Time since precipitating event, duration (time 
since onset of symptoms), and time since diagnosis will be calculated based on the date of Visit 1 
and the corresponding CRPS-related dates reported in the eCRF, and will be summarized as 
continuous variables. Time will be displayed in years. The CRPS etiology (precipitating event), 
CRPS location, previous CRPS history, and imaging methods used to support prior diagnosis (or 
exclude other diagnoses) will be categorically summarized.
11.4
Prior and concomitant medication or therapy
Therapies will only be displayed in the subject data listings.
Prior and concomitant medication is collected in the eCRF 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. In addition, the number of subjects 
with medication started after last dose of IMP will be displayed. 
Medication or therapy started after last dose of IMP will be flagged in the subject data listing.
12
EXPOSURE AND COMPLIANCE
Exposure and compliance will be analyzed overall, i.e., for the single treatment group neridronic 
acid 400 mg, for the SAF.
All exposure and compliance data will be presented in subject data listings.
12.1
Exposure
At each infusion visit (Visits 2, 3, 4, and 5), the full contents of an 8 mL ampule or vial will be 
transferred to an infusion bag containing 500 mL normal saline and administered by slow 
intravenous infusion.
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The volume of IMP transferred to the infusion bag, the administered volume of the infusion, and the 
dose (amount of neridronic acid) and the cumulative dose will be listed by visit. For dose and 
cumulative dose, the actual and the planned dose will be displayed. 
Actual dose and actual cumulative dose will be descriptively summarized by visit.
12.2
Compliance
At each infusion visit (Visits 2, 3, 4, and 5), compliance (%) will be calculated as the ratio of the 
dose actually administered, divided by the planned dose (100 mg). Moreover, the cumulative 
compliance will be derived at each infusion visit as the ratio of the actual cumulative dose divided 
by the planned cumulative dose. Compliance and cumulative compliance will be descriptively 
summarized by visit.
Cumulative compliance at Visit 5 will be classified based on the following 4 intervals 0 - 25%, 
>25 - 50%, >50 - 75%, and >75% - 100%, and a descriptive summary will be presented.
In addition, a categorical summary of infusion data in the eCRF (questions “Was the IMP 
administered to the subject?”, and “Was dose completely administered?”) will be created by visit.
13
EFFICACY ANALYSES
All efficacy data will be analyzed overall, i.e., for the single treatment group neridronic acid 
400 mg, for the FAS, unless specified otherwise.
All efficacy data will be presented in subject data listings.
Missing efficacy data will not be imputed in this trial. The number of missing values will be 
included in all descriptive summaries.
13.1
Primary endpoint
Not applicable. No primary efficacy endpoint is defined for this trial.
13.2
Secondary endpoints
All secondary efficacy endpoints will be analyzed for the FAS and additionally for the TCS.
The following secondary efficacy endpoints will be analyzed overall and by subgroups:
•
Change from baseline to Week 12 and Week 26 in the current pain intensity score, using a 
numerical rating scale (NRS).
•
Response to treatment, defined as at least 30%, at least 50% and at least 2 points on the 
NRS decrease from baseline in the current pain intensity score, at Week 12 and Week 26.
•
Patient Global Impression of Change (PGIC) at Week 12 and Week 26.
•
Change from baseline to Week 12 and Week 26 in the Pain Interference score of the Brief 
Pain Inventory (BPI).
Since this is a single-arm trial, no hypothesis testing of secondary efficacy endpoints between 
treatment arms is planned. All secondary efficacy endpoints will be analyzed descriptively. 
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13.2.1
Main analysis
This section defines the main analysis for the secondary efficacy endpoints.
13.2.1.1
Current pain intensity
Current pain intensities and the corresponding changes from baseline will be presented in a subject 
data listing. Baseline current pain intensities will be flagged in the listing. Current pain intensities 
including their changes from baseline will be descriptively summarized by visit.
The change from baseline values at all post-baseline visits from Visit 3 through Visit 11 will be 
analyzed using a mixed model for repeated measures (MMRM), including the covariate baseline 
pain intensity, and the factors pooled site and visit as fixed effects, and subject as random effect. An 
unstructured covariance matrix will be used to model the covariance structure. The degrees of 
freedom of the denominator will be estimated using the Kenward-Roger approximation (Kenward 
and Roger 1997).
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=9 is the total number of post-baseline visits, visits 3 to 11) 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.
Point estimates (LSmeans), standard errors, and 95% CIs for the factor visit in the MMRM model 
representing the change from baseline at each visit will be presented. A graphical plot of the model-
based estimates and the 95% CI of the change from baseline of current pain intensity scores will be 
created. 
13.2.1.2
Response to treatment
For each subject, the percentage change from baseline in current pain intensity will be calculated at
each post-baseline visit (Visit 3 through Visit 11):
%ℎ	
 =  
 −



∙100%.
If the decrease is at least 30%, at least 50%, or at least 2 points on the NRS, the subject will be 
considered a responder for the respective threshold. If a subject shows a worsening or the pain 
intensity score is missing, the subject will not be considered a responder. This applies also to 
subjects with premature discontinuation where subsequent pain values are missing. 
The percentage change from baseline, and the responder status (responder Yes/No) with respect to 
the 3 responder definitions will be presented in a subject data listing.
Descriptive summaries of the responder status will be presented by visit for each of the 3 responder 
definition. This includes the summary of the secondary responder endpoints, i.e., the response to 
treatment defined as at least 30%, at least 50% and at least 2 points on the NRS decrease from 
baseline at Week 12 (Visit 8) and Week 26 (Visit 9).
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A graphical plot of the responder rates will be created by responder definition and visit.
For each of the 3 responder definitions, persistence of the treatment effect will be assessed by 
deriving a combined responder status for the following 3 time periods:
•
Months 3 and 6 (Visit 8, and 9).
•
Months 3, 6, and 9 (Visit 8, 9, and 10).
•
Months 3, 6, 9, and 12 (Visit 8, 9, 10, and 11). 
A subject is a combined responder if he/she is a responder at each of the visits mentioned in the 
definition of the respective time period. For the derivation of the combined responder status, the 
results of the individual visits are combined.
13.2.1.3
Patient Global Impression of Change
The PGIC will be assessed at Visit 7 through Visit 11. 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). A 
response of “very much improved” or “much improved” is generally regarded as a clinically 
important outcome. The response to treatment based on the PGIC will be derived by classifying 
subjects with outcome “very much improved” or “much improved” as responders, and subjects with 
other outcomes as non-responders. Subjects with missing PGIC score will be considered as non-
responders.
All PGIC scores and the derived responder status will be presented in a subject data listing.
A descriptive summary of the categorical PGIC scores and the responder status will be generated by 
visit. This includes the summary of the secondary PGIC endpoints at Week 12 and Week 26.
A graphical plot of the distribution of the PGIC will be created by visit.
13.2.1.4
Brief Pain Inventory
Subjects will complete the brief pain inventory (BPI) Interference Scale questionnaire at Visit 2 and 
Visit 7 through Visit 11. 
The BPI is a multi-item scale measuring the impact of pain on functioning and well-being. The 
7 pain interference items: general activity, walking, work, mood, enjoyment of life, relations with 
others, and sleep, are each rated on a 0 to 10 scale using a 24-hour recall period, with 0 indicating 
“does not interfere” and 10 indicating “completely interferes”. 
The total Pain Interference Score is calculated by adding the scores for the 7 questions and dividing 
by 7, i.e., the average of the 7 item scores. This gives an interference score with a range from 0 to 
10. If not more than 3 of the 7 items are missing, the average is calculated based on the available 4, 
5, or 6 item scores. If more than 3 of the 7 items are missing, the total score will not be calculated 
and is considered missing.
The scale can also be subdivided into activity (general activity, walking, work and sleep) and 
affective (mood, enjoyment of life, relations with others) subcomponents. For the activity and
affective subcomponents, the subcomponent score will not be calculated and is considered missing 
if 1 of the item scores is missing.
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All individual item BPI scores, the subcomponent scores, and the total score will be presented in a 
subject data listing.
A descriptive summary of the categorical individual item scores will be generated by item and visit. 
Furthermore, a descriptive summary of the continuous subcomponent scores and the continuous 
total score, and the corresponding changes from baseline will be generated by score type 
(subcomponent scores, and the total score) and visit. This includes the summary of the secondary 
BPI endpoints at Week 12 and Week 26.
13.2.2
Sensitivity analysis
Not applicable.
13.2.3
Other analysis
Not applicable.
13.3
Analysis of other efficacy data
The following outcome parameters based on other efficacy data collected in this trial will be 
analyzed for the FAS:
•
Change from baseline to Week 12 and Week 26 in the worst pain intensity score, using an 
11-point NRS.
•
Change from baseline to Week 12 and Week 26 in the average pain intensity score, using 
an 11-point NRS.
•
Change from baseline to Week 12 and Week 26 in the Pain Disability Index (PDI) score.
•
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 12 and Week 26 in the Pain Anxiety Symptom Scale 
(PASS) score.
•
Change from baseline to Week 12 and Week 26 in the Center for Epidemiological Studies 
Depression Scale (CES-D) score.
•
Change from baseline to Week 12 and Week 26 in the CRPS Severity Score.
13.3.1
Average and worst pain intensity
Worst and average pain intensities will be added to the subject data listing of current pain values 
(see Section 13.2.1.1). The listing will be presented by pain type (average, current, and worst). 
Worst and average pain intensities will be added to the descriptive summary of current pain. The 
summary will be presented by pain type.
Change in the worst pain intensity and average pain intensity for all post-baseline visits will be 
analyzed using the same statistical model as the one used for the current pain. 
Point estimates least square means (LSmeans), standard errors, and 95% CIs for the factor visit in
the MMRM model representing the change from baseline at each visit will be presented. Results 
will be added to the model-based summary of current pain.
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Graphical plots of the model-based estimates and the 95% CI of the change from baseline of worst 
and average pain intensity will be created. The plots will be added to the graphical plots of current 
pain intensity scores.
13.3.2
Pain Disability Index score
The PDI questionnaire will be completed by all subjects at Visit 2 and Visit 7 through Visit 11. 
The PDI questionnaire includes questions related to pain-related disability in 7 categories: 
family/home responsibilities, recreation, social activity, occupation, sexual behavior, self-care, and 
life-support activities. For each of the 7 categories, the subjects are asked to rate on an 11-point 
NRS the level of disability they typically experience. The PDI is calculated as the sum of the 
7 categories, for a minimum value of 0 and maximum value of 70. If one of the 7 items is missing 
the PDI score will not be calculated and is considered missing.
All individual PDI categories and the total score will be presented in a subject data listing.
A descriptive summary of the categorical individual category scores will be generated by visit. 
Furthermore, a descriptive summary of the continuous total score and the corresponding changes 
from baseline will be generated by visit. This includes the summary of the PDI score at Week 12 
and Week 26.
13.3.3
EuroQoL-5 dimension 5 level score and VAS
The EQ-5D-5L health questionnaire will be completed by all subjects at Visit 2 and Visit 7 through 
Visit 11. 
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).
All five EQ-5D-5L dimensions, the EQ-5D-5L index, and the EQ VAS will be presented in a 
subject data listing.
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. This includes the summary 
of the EQ-5D-5L index and the EQ VAS at Week 12 and Week 26.
13.3.4
Pain Anxiety Symptom Scale
The PASS questionnaire will be completed by all subjects at Visit 2 and Visit 7 through Visit 11. 
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The PASS questionnaire consists of 20 items designed to assess 4 aspects of pain-related anxiety: 
cognitive anxiety, escape-avoidance behaviors, fear of pain, and physiological symptoms of 
anxiety. Subjects rate each item in terms of frequency, from 0 (never) to 5 (always). The total score 
is calculated as the sum of ratings, with values ranging from 0 to 100; higher scores indicate higher 
levels of pain-related anxiety. If 1 of the 20 items is missing, the total score will not be calculated 
and is considered missing. A similar rule is applied to missing items in the calculation of the 
subcomponents. The subcomponents are defined in terms of the following item subsets (McCracken 
and Dhingra 2002):
•
Cognitive anxiety: items 5, 10, 14, 17, and 19.
•
Escape-avoidance behaviors: items 3, 6, 8, 11, and 20.
•
Fear of pain: items 1, 2, 9, 13, and 16.
•
Physiological symptoms of anxiety: items 4, 7, 12, 15, and 18.
All individual item PASS scores, the subcomponent scores, and the total score will be presented in 
a subject data listing.
A descriptive summary of the categorical individual item scores will be generated by visit. 
Furthermore, a descriptive summary of the 4 continuous subcomponent scores, the continuous total 
score, and the corresponding changes from baseline will be generated by visit. This includes the 
summary of the PASS total score at Week 12 and Week 26.
13.3.5
Center for Epidemiological Studies Depression Scale score
The CES-D questionnaire will be completed by all subjects at Visit 2 and Visit 7 through Visit 11.
The 20 items of the scale are symptoms associated with depression. Subjects are asked to rate each 
item from “rarely or none of the time (less than 1 day)” to “most or all of the time (5 to 7 days)” 
during the last week. Response scores for all questions except 4, 8, 12, and 16 are: <1 day = 0; 
1-2 days = 1; 3-4 days = 2; 5-7 days = 3. For question 4, 8, 12, and 16, the scoring is reversed, i.e., 
<1 day = 3; 1-2 days = 2; 3-4 days = 1; 5-7 days = 0. The total CES-D score is calculated as the sum 
of scores for all 20 questions and has a range of 0 to 60. If of the 20 items is missing, the CES-D 
score will not be calculated and is considered missing.
All individual CES-D items and the total score will be presented in a subject data listing.
A descriptive summary of the categorical individual item scores will be generated by visit. 
Furthermore, a descriptive summary of the continuous total score and the corresponding changes 
from baseline will be generated by visit. This includes the summary of the CES-D total score at 
Week 12 and Week 26.
13.3.6
Complex Regional Pain Syndrome Severity Score
Signs and symptoms of CRPS will be assessed by the investigator at Visit 1 (enrollment), at Visit 2 
(baseline) and Visit 7 through Visit 11 and recorded using the electronic patient reported outcome 
system. 
The investigator examines the signs. The subjects are asked to report their symptoms with a recall 
period of 48 hours. At the Enrollment Visit, subjects are additionally asked to report their symptoms 
with a recall period since onset of disease for purposes of establishing the diagnosis of CRPS. This 
information is also used, in combination with the investigators assessment of signs of CRPS at 
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Visits 9, 10 and 11, to determine whether or not the subject continues to meet criteria for a 
diagnosis of CRPS at these latter visits (Table 2).
Table 2: 
Assessments of CRPS signs and symptoms
Enrollment
Baseline
Post-baseline
Visit 1
Visit 2
Visit 7 – Visit 11
Symptoms (recall period 
since onset) a
X
(X c)
Symptoms (recall period 
48 hours) b
X
X
X
Signs
X
X
X
a) Used for establishing the diagnosis of CRPS.
b) Used for CRPS severity score.
c) Values copied from Visit 1.
CRPS = complex regional pain syndrome.
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): 
9.
Hyperalgesia to pinprick.
10. Allodynia.
11. Temperature asymmetry by palpation.
12. Skin color asymmetry.
13. Asymmetric edema.
14. Sweating asymmetry.
15. Dystrophic changes.
16. Motor abnormalities. 
Each sign or symptom is assigned a dichotomous value (1 = YES/presence; 0 = NO/absence). To 
derive the CRPS severity score, the symptoms reported with recall period 48 hours and the signs 
will be added. The resulting CRPS severity score ranges from 0 to 16. If the value for 1 of the 
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16 signs and symptoms is missing, the CRPS severity score will not be calculated and is considered 
missing.
The presence of CRPS at post-baseline Visits 7 to Visit 11 will be derived based on the “Budapest 
clinical diagnostic criteria” (Harden et al. 2010). For the Budapest criteria to be fulfilled, 3 criteria 
must be verified. The criteria are linked to the symptoms with recall period since onset and the signs 
in the following way:
1.
Criterion (1): question 1 answered YES
2.
Criterion (2): at least 3 of the following 4 symptom categories must be fulfilled:
•
Sensory: question 2  answered YES
•
Vasomotor: question 3 or question 4 answered YES
•
Sudomotor/edema: question 5 or question 6 answered YES
•
Motor/trophic: question 7 or question 8 answered YES
3.
Criterion (3): at least 2 of the following 4 sign categories must be fulfilled
•
Sensory: question 9 or question 10 answered YES
•
Vasomotor: question 11 or question 12 answered YES
•
Sudomotor/edema: question 13 or question 14 answered YES 
•
Motor/trophic: question 15 or question 16 answered YES
A subject data listing will present for:
•
The individual signs and symptoms values (YES/NO).
•
The answers to follow-up questions in case a sign or symptom is present.
•
The CRPS severity score.
•
The presence/absence of CRPS (Visits 7 through Visit 11).
•
Comments.
A descriptive summary will be created by sign/symptom and visit for:
•
The dichotomous symptoms and signs,.
•
The dichotomous CRPS assessment (present/absent). 
For the Enrollment Visit, symptoms with recall period since onset and symptoms with recall period 
48 hours will both be summarized. A graphical display of the proportion of affected subjects over 
the entire 12-month trial period will be created including:
•
The proportion of subjects with a sign/symptom, for each of the symptoms with recall 
period 48 hours and for each of the signs.
•
The proportion of subjects meeting the diagnosis of CRPS, i.e., with CRPS presence.
Furthermore, a descriptive summary of the continuous CRPS severity score and the corresponding 
change from baseline will be generated by visit. A graphical plot of the means and 95% CI of the 
CRPS severity score over the entire 12-month trial period will be created.
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14
ANALYSIS OF PHARMACOKINETIC AND 
PHARMACODYNAMICS PARAMETERS
In the following sections, a detailed description of all calculations and statistical methods used in 
the analysis of pharmacokinetic and pharmacodynamic parameters is presented.
Descriptive and graphical methods will be used to summarize the trial results.
Summaries will be grouped by treatment and time of assessment.
Missing data will be treated as such and will not be imputed or replaced in any way if not specified 
otherwise. 
14.1
Analysis of pharmacokinetic data
Not applicable. 
14.2
Analysis of pharmacodynamic data
Pharmacodynamic data comprise bone turnover markers and data from bone densitometry and MRI
procedures. The analysis of pharmacodynamic data is described in the following sections.
14.2.1
Bone turnover markers
Bone turnover markers will be analyzed in the Pharmacodynamic Set.
The following bone turnover markers are assessed at Visit 2 and at Visits 6, 7, 8, 9, 10, and 11:
•
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, including changes from baseline, will be descriptively summarized by 
time point.
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.
14.2.2
Bone densitometry and magnetic resonance imaging procedures
Data collected in the electronic case report form (eCRF) will be listed for all subjects in the Bone 
Imaging Set. No further statistical analysis is planned in this SAP. Bone densitometry and MRI data 
will be analyzed and reported separately by a dedicated bone imaging service provider.
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15
SAFETY ANALYSES
Safety data will be summarized descriptively overall, i.e., for the single treatment group neridronic 
acid 400 mg.
All safety data will be presented for the SAF unless otherwise specified. 
15.1
Adverse events
All adverse events with start date/time after first IMP administration in a subject administered a trial 
treatment will be defined as treatment emergent adverse events (TEAE) irrespective of causal 
relationship. 
A pre-treatment non-TEAEs 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 20.1.6.1.
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
A TEAE is considered to be ‘expected’ when the nature or intensity is consistent with the 
information in the neridronic acid investigator’s brochure. Otherwise, it is considered to be an 
‘unexpected’ TEAE. Expectedness will be assessed by the sponsor.
The following overview tables will be generated overall, i.e., for the single treatment group 
neridronic acid 400 mg.
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 TEAEs.
•
TEAE leading to discontinuation from IMP.
•
TEAE leading to discontinuation from the trial.
•
Deaths.
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The percentage denominator will be the number of subjects. 
2.
Summary presenting the number of TEAEs per subject categorized as 0, 1, 2, 3, 4, 5, and >5. 
3.
Summary of the number and percentage of TEAEs for:
•
TEAEs.
•
Serious TEAEs.
•
Non-serious TEAEs.
•
Unexpected TEAE.
•
Related TEAEs.
•
Related serious TEAEs.
•
TEAE leading to discontinuation from IMP.
•
TEAE leading to discontinuation from the trial.
The percentage denominator will be the total number of TEAEs. 
If more than 10 subjects discontinue the trial/IMP due to TEAE, the incidence and the incidence 
rate of TEAEs leading to discontinuation from the trial/from IMP will be summarized by SOC and 
PT.
If more than 5% of the subjects discontinue the trial due to TEAE, the distribution of the time to 
discontinuation from trial due to TEAE will be summarized using time-to-event methods. Time will 
be days until discontinuation. The time to discontinuation will be censored at the End-of-Trial Visit
or at the time point of discontinuation if not due to TEAE.
If more than 5% of the subjects permanently discontinue IMP due to TEAE, the distribution of the 
time to discontinuation from IMP due to TEAE will be summarized using time-to-event methods. 
Time will be days until discontinuation. The time to discontinuation will be censored at the last 
planned infusion visit (Visit 5), or at the time point of discontinuation, whichever occurs first.
15.1.1
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 (CIR for crude incidence rate) 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 (related to the total 
number of events) will be summarized by PT sorted by decreasing incidence rate for:
•
TEAEs.
•
Serious TEAEs.
•
Non-serious TEAEs.
•
Related TEAEs.
A separate table per type of TEAE will be prepared. The tables will be restricted to events with an 
incidence rate of at least 5% (≥5%).
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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:
•
TEAEs.
•
Serious TEAEs.
•
Non-serious TEAEs.
•
Related TEAEs.
For serious TEAEs, the incidence, the incidence rate, the number of events and the percentage of 
events will also be presented for serious related TEAEs, serious fatal TEAEs and serious fatal 
related TEAEs.
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. Presentation will be for TEAEs only.
•
Intensity: mild, moderate, severe.
•
Causal relationship to the IMP: related (with subcategories: possible, probable/likely, 
certain), not related (with subcategories: not related, unlikely), unknown (with 
subcategories: 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, not applicable, unknown.
Denominator for percentage calculation will be the number of all TEAEs for presentation 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. 
In addition, the time to onset of TEAE will be summarized using time-to-event methods pooled 
over all TEAEs. Time will be days until onset. The time to onset will be censored at the End-of 
Trial-Visit, or at the time point of discontinuation if not due to TEAE.
The following listings will be produced for all enrolled subjects: 
•
Deaths.
•
Serious adverse events other than death.
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•
Adverse events leading to discontinuation from the trial.
•
Adverse events leading to permanent discontinuation from IMP.
In addition, adverse events associated with acute phase reaction will be presented for the SAF in a 
separate subject data listing. Adverse events associated with acute phase reaction include the PTs
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 first IMP intake 
and not lasting longer than 3 days.
For TEAEs associated with the acute phase reaction, the incidence, incidence rate, the number of 
events and the percentage of events (related to the total number of events) will be summarized by 
PT.
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, if 
applicable, by time point.
Categorical parameters will be descriptively summarized by presenting the number and percentage 
of subjects per visit/time point, and overall post-baseline. For an overall post-baseline analysis, the 
worst value during the on-treatment period, including unscheduled visits, will be derived.
Continuous parameters will be descriptively summarized. Change from baseline will be presented
for all post-baseline visits/time points. Baseline values are defined as described in Section 8.2.2. If 
reference ranges for a parameter differ between subject groups, e.g., based on sex or age group, the 
analysis of the parameter will be presented separately for each subject group.
Continuous parameters will be classified as low, normal, or high based on reference ranges, and for 
parameters where sponsor alert ranges are defined, parameters will be classified as alert low, non-
alert, or alert high based on sponsor-defined alert ranges. For an overall post-baseline analysis, the 
values out of range during the on-treatment period, including unscheduled visits, will be 
summarized per subject. If a subject has parameter values flagged as low and values flagged as 
high, the parameter will be classified as low+high. 
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 where 
sponsor alert ranges are defined at each visit/time point and overall post-baseline. 
Shift tables from baseline for the different visits /time points and overall post-baseline will be 
generated for each continuous parameter flagged as low, normal, or high with respect to reference 
ranges. Percentages will be calculated for each baseline category (low, normal, or high) using the 
number of subjects in the corresponding post-baseline categories. 
Graphical presentations of the time course of continuous parameters and corresponding changes 
from baseline will be provided (mean and 95% confidence interval). At each visit/time point, the 
plots will show the total number of subjects. 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 sponsor-defined alert ranges will be shown by treatment.  
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Shift plots by visit/time point will be provided for the 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. For continuous parameters, values 
out of reference ranges will be flagged as H (high) or L (low) in the listing. If a value classified as 
high or low is in addition also out of sponsor-defined alert ranges, it will be flagged as H* or L* in 
the listing.
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
Central laboratory parameters will be analyzed as described in the following paragraphs. Local 
laboratory assessments, pregnancy tests, and drugs of abuse tests will only be listed.
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. The corresponding analyses of these parameters will be repeated using 
values in US conventional units. The list of parameters will be provided in a separate spreadsheet
attached to the data management plan.  
Continuous and categorical laboratory parameters will be analyzed as described in Section 15.2
with individual specifications outlined in Table 3. The analysis of continuous laboratory parameters 
will be done by parameter group (clinical chemistry, clotting, hematology, and urinalysis). 
Categorical urinalysis parameters will be additionally classified as normal or abnormal.
Graphical presentations of the mean time course of the continuous parameters alkaline phosphatase, 
calcium (measured), creatinine (serum), estimated glomerular filtration rate (eGFR), and calculated
urinary albumin/creatinine will be provided (mean and 95% CI). The graph covers the 12-month
trial period presenting the means from Visit 1 through Visit 11. Similarly, a graphical presentation 
of the mean time course of the change from baseline of the 5 parameters will be provided. The 
mean time course of each parameter and the corresponding change from baseline will be presented 
in 1 plot. The plots will be presented in US conventional units.
Shift plots by visit will be provided for the same parameters. The plots will be presented in US 
conventional units.
A graphical presentation of the mean time course of the laboratory parameters serum calcium 
(measured), urinary calcium and parathyroid hormone, and the bone turnover marker BAP 
(Section 14.2.1) will be created (mean and 95% CI). The 4 mean plots will presented as a single 
panel plot on the same page. The plot will be presented 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.
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Table 3:
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
Bicarbonate
X
X
X
BUN
X
X
X
Calcium (measured)
X
X
X
X
X
Calcium (albumin-
corrected)
X
X
X
Chloride
X
X
X
Cholesterol
X
X
X
Creatine 
phosphokinase
X
X
X
Creatinine (serum)
X
X
X
X
X
eGFR
X
X
X
X
X
GGT
X
X
X
Glucose
X
X
X
LDH
X
X
X
Lipase
X
X
X
Magnesium
X
X
X
Parathyroid hormone
X
X
X
X
X
Phosphorus
X
X
X
Potassium
X
X
X
Sodium
X
X
X
Total bilirubin
X
X
X
Total protein
X
X
X
Triglycerides
X
X
X
Uric acid
X
X
X
Vitamin D
X
X
X
X
X
Hematology 
parameters 
(continuous)
Hematocrit
X
X
X
Hemoglobin
X
X
X
MCH
X
X
X
MCHC
X
X
X
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Parameter 
group
Parameter
Table of 
descriptive 
statistics
Frequency 
table 
(low/high)
Shift table
Mean plot
Shift plot
MCV
X
X
X
Platelet count
X
X
X
RBC count
X
X
X
WBC count a
X
X
X
Urinalysis 
parameters 
(continuous)
Albumin 
(miroalbumin)
X
X
X
Calcium
X
X
X
X
X
Creatinine
X
X
X
Calculated urinary 
albumin/creatinine 
ratio
X
X
X
X
X
pH b
X
X
X
Urinalysis 
parameters 
(categorical)
Bilirubin b
X
X
Blood (erythrocytes) b
X
X
Glucose b
X
X
Ketone b
X
X
Leukocyte esterase b
X
X
Nitrite b
X
X
Protein b
X
X
Urobilinogen b
X
X
a) With differential count if abnormal: includes neutrophils, lymphocytes, monocytes, basophils, eosinophils (absolute 
count and percent).
b) Dipstick assessment.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; eGFR = estimated 
glomerular filtration rate; GGT = gamma-glutamyl transferase; LDH = lactic acid dehydrogenase; MCH = mean 
corpuscular hemoglobin; MCHC = mean cell hemoglobin concentration; MCV = mean cell volume; RBC = red blood 
cell; WBC = white blood cell.
On Day 1, Day 4, Day 7, and Day 10, additional urine samples will be obtained prior to infusion for 
local laboratory assessment of urinary albumin creatinine ratio (ACR) at the site using a semi-
quantitative dipstick. The results will be presented in a subject data listing.
If a dipstick test is positive (except for glucose or ketones, and blood/leucocytes in menstruating 
subjects), a microscopic examination of urine sediment will be performed to determine the presence 
of red blood cells, white blood cells, epithelial cells, crystals, casts, and bacteria. The results will be 
presented in a subject data listing.
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Urine samples will be obtained from women of child-bearing potential (Visit 1 through Visit 5, 
Visit 9, and Visit 11) and 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
Vital signs comprise systolic and diastolic blood pressure, pulse rate, respiratory rate, body weight,
and BMI. Vital signs will be measured at each visit (Visit 1 to Visit 11). At Visit 2 through Visit 5, 
vital signs will be taken once at least 15 minutes before the infusion and once at least 15 minutes 
after the infusion. Body weight will be included as a vital sign and will be measured at all visits 
(only once at Visit 2 through Visit 5, prior to the infusion). BMI will be derived.
Vital signs parameters will be analyzed as described in Section 15.2 with individual specifications 
outlined in Table 4.
Table 4:
Analysis of vital signs parameters
Parameter
Table of 
descriptive 
statistics
Frequency 
table 
(low/high)
Shift table
Mean plot
Shift plot
Vital signs
parameters 
(continuous)
Blood pressure 
(diastolic)
X
X
X
Blood pressure 
(systolic)
X
X
X
BMI a
X
X
X
Body weight
X
X
X
Pulse rate
X
X
X
Respiratory rate
X
X
X
a) BMI will be derived.
BMI = body mass index.
15.2.3
Electrocardiogram
Twelve-lead ECGs will be recorded from Visit 1 to Visit 6, at Visit 9, and at Visit 11. At Visit 2 
through Visit 5, triplicate ECGs will be recorded once at least 15 minutes before the infusion and 
once at least 15 minutes after the infusion. One triplicate ECG will be recorded at all other visits.
Electrocardiogram parameters will include heart rate and the following ECG intervals: QRS, PR, 
RR, QT, QTcB, and QTcF. Twelve-lead ECGs are recorded in triplicate. For the analysis, the mean 
of the 3 individual values will be calculated for each parameter.
Electrocardiogram (ECG) parameters (continuous) will be analyzed as described in Section 15.2
with individual specifications outlined in Table 5.
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Table 5:
Analysis of ECG parameters
Parameter
Table of 
descriptive 
statistics
Frequency 
table 
(low/high)
Shift table
Mean plot
Shift plot
ECG
parameters 
(continuous)
Heart rate
X
X
X
PR interval
X
X
X
QRS interval
X
X
X
QT interval
X
X
X
QTcB interval
X
X
X
QTcF interval
X
X
X
RR interval
X
X
X
ECG = electrocardiogram; QTcB = Corrected QT interval (according to Bazett’s formula); QTcF = Corrected QT 
interval (according to Fridericia’s formula).
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 eCRF will be created.
15.3
Physical examination
Physical examination outcomes will be recorded at Visit 1, before the IMP infusion at Visit 2, and 
from Visit 8 through Visit 11 in the follow-up period. 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 is recorded by rating each body system as unchanged or changed.
All physical examination results will be presented in a subject data listing.
15.4
Bone biopsy procedures
Data collected in the eCRF regarding bone biopsy procedures and tetracycline intake will be listed 
for all subjects in the Bone Biopsy Set. No further statistical analysis is planned in this SAP. Bone 
biopsy data will be analyzed and reported separately by a dedicated bone biopsy service provider.
15.5
Primary endpoint
The primary endpoint of this trial is a binary safety endpoint assessing whether or not a subject 
experienced any TEAE. The incidence and incidence rate for any TEAE is included in the summary 
of the number and percentage of subjects with TEAE (Section 15.1).
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15.6
Secondary safety endpoint
The secondary safety endpoint is the occurrence of permanent discontinuation from treatment due 
to an adverse event. The number and percentage of subjects permanently discontinued from 
treatment is included in the summary of discontinuations from IMP (Section 10.2).
16
HEALTH ECONOMICS OUTCOME AND WORK PRODUCTIVITY 
DATA
The health economics outcome and work productivity data will only be collected for subjects in US 
sites. The following questionnaires will be collected:
•
Work Productivity and Activity Impairment Questionnaire: CRPS (WPAI: CRPS) 
assessment on Day 1, at Week 26, and at Week 52.
•
Medical resources utilization and health economics data collection on Day 1, at Week 26, 
and at Week 52.
All data will be analyzed overall, i.e., for the single treatment group neridronic acid 400 mg, for the 
FAS. All data will be presented in subject data listings.
16.1
Work Productivity and Activity Impairment Questionnaire: CRPS
Answers to the 6 questions of the WAPI: CRPS questionnaire will be descriptively summarized by 
visit. The answers to question 1 (Are you currently employed: Yes/No?) will be assigned a 
dichotomous value (1 = Yes; 0 = No) and summarized as a continuous variable, i.e., the proportion 
of employed subjects will be derived.
16.2
Medical resources utilization and health economics data
The medical resources utilization and health economics questionnaire has 6 categories: 
•
Hospitalization.
•
Emergency room visit.
•
Nursing home stay.
•
Outpatient care provider contact.
•
Home services and help.
•
Special product/device/tool.
For the categories hospitalization, emergency room visit, nursing home stay, and special 
product/device/tool, the use of these services will be descriptively summarized as a categorical 
variable (Yes/No/Don’t know).
For the categories outpatient care provider contact, and home services and help, the use of each 
service type within the 2 categories will be descriptively summarized as a categorical variable 
(Yes/No/Don’t know). 
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17
INTERIM ANALYSIS
17.1
Interim analysis of efficacy
Not applicable.
17.2
Interim analysis of safety 
An external, independent DMC will periodically review safety information from the trial and 
monitor trial conduct and overall progress.
The DMC will have the ability to make recommendations to the sponsor that might impact the 
future conduct of the trial. Procedures for and management of the DMC will follow the sponsor’s 
standard operating procedures and will be documented in the DMC Charter. The DMC for this trial 
is anticipated to convene approximately every 6 months, depending on subject accrual in the trial.
The safety analyses provided to the DMC for each review meeting will be defined in a separate 
SAP. 
18
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.
Clinical Data Interchange Standards Consortium (CDISC) Submission Data Standards Team. Study 
Data Tabulation Model Implementation Guide: Human Clinical Trials. Version 3.2, 2013.
EuroQol: http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-sets.html (last 
accessed 29 September 2016).
Food and Drug Administration: Guidance for Industry. Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation; July 2009.
Harden RN, Bruehl S, Perez RS, Birklein F, Marinus J, Maihofner C, et al. Validation of proposed 
diagnostic criteria (the ‘‘Budapest Criteria”) for Complex Regional Pain Syndrome. Pain 2010; 
150(2): 268-74.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997; 53(3): 983-97.
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.
McCracken LM, Dhingra L. A short version of the Pain Anxiety Symptoms Scale (PASS-20): 
Preliminary development and validity. Pain Res Manage 2002; 7(1): 45-50.
SDN-NONCOMP-DEF-01 Definitions of Non-compliances.xlsm
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19
CHANGES TO THE SAP
19.1
Changes from pre-final to final version
Not applicable.
19.2
Amendments
Changes were made from Final SAP (Version 1.0) to SAP Amendment 01 (Version 2.0). All the 
changes are documented in Section 7.3.
20
APPENDIX
20.1
Data derivation and analysis rules
The purpose of this section is to give technical details for the implementation of the SAP.
20.1.1
General specifications
20.1.1.1
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 (CI) and standard deviation (SD).
•
P-values are presented to 3 decimal points. P-values <0.001 will be reported as such.
•
Ratios are presented to 3 decimal points.
The above described displaying rules must not be changed (e.g., rounding) for the integrated 
clinical trial report (ICTR) text and are used 1:1 in the body report as well. For analysis of 
pharmacokinetic data see also Section 20.1.5.
20.1.1.2
Presentation of descriptive statistics
Calculation of mean: if not otherwise specified, the arithmetic mean is used.
Table 6:
Presentation of descriptive statistics in clinical trials
Number of non-
missing values
n
Missing n
Mean
SD
Min
Q1
Median
Q3
Max
{CI for mean}
0
+
+
-
-
-
-
-
-
-
-
1.2.3.4
+
+
+
-
+
-
+
-
+
-
≥5
+
+
+
+
+
+
+
+
+
+
+ summary statistic will be presented;  - summary statistic will not be presented.
n = number of values; Min = minimum; Max = maximum; SD = standard deviation; Q1 = first quartile; Q3 = third 
quartile.
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20.1.1.3
Presentation of differences and changes
For changes from baseline, the post-baseline value will constitute the minuend and the baseline 
value the subtrahend, i.e., change = value - baseline. 
20.1.1.4
Trial day count
The day of allocation/baseline visit / first IMP 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
20.1.1.5
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 ([ ]).
20.1.1.6
Presentation of dates
Where applicable (e.g., in listings), dates will be displayed in ISO8601 format (example: 2014-09-
29T12:16, see CDISC 2013 V3.2). In case of incomplete dates, both the original value and the 
imputed value are displayed.
20.1.1.7
Handling of missing values
At each time point/visit, all subjects still in the trial are reported. Missing values will be taken into 
account as missing in the analysis. The number of observed values and the number of missing 
values must sum up to the number of subjects in the trial at the respective time point/visit.
Missing measurements/missing values are identified by the SDTM variable **STAT=ND. If this 
variable is not recorded (it’s a permissible variable) the missing values of **ORRES should be 
used.
Unless otherwise specified in the SAP, missing values will not be imputed.
20.1.1.8
Visit windows
Not applicable.
20.1.1.9
Assessments of on-treatment-period
For the calculation of the on-treatment-period the date and time information given for IMP 
administration will be used according the definition in Section 8.2.2.
20.1.1.10
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
20.1.1.11
End of treatment 
End of treatment is the date of last administration of IMP given on the End-of-trial page in the 
eCRF. 
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20.1.1.12
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”.
20.1.1.13
Kaplan-Meier analysis
No additional specifications.
20.1.1.14
Handling of data from early termination visits
Subjects who discontinue during the trial the before their Visit 11 will be requested to undergo an 
early termination visit with identical procedures to Visit 11. Procedures done at Visit 11 are listed in 
the schedule of events of the protocol.
If the last available visit is between Visit 2 and Visit 7, data from the early termination visit will be 
assigned to the next scheduled visit; otherwise data will be assigned to the nearest scheduled visit 
based on the trial day of the early termination visit and the planned visit day. The planned visit day 
is:
•
Day 182 for Visit 9 (Week 26).
•
Day 273 for Visit 10 (Week 39).
•
Day 365 for Visit 11 (Week 52).
In case of equal distance to 2 scheduled visits, the earlier visit will be chosen. If the assigned visit 
already occurred before the early termination visit, the data will be assigned to the next scheduled
visit.
Data from the early termination visit will be analyzed using the re-assigned visits.
20.1.2
Disposition
20.1.2.1
Subject discontinuation
Reasons for subject discontinuation from trial/IMP as specified in the End-of-Trial/Treatment 
Completer pages of the eCRF will be used.
20.1.2.2
Protocol deviations
Protocol deviations are based on the analysis dataset ADDV. Key and major protocol deviations are 
retrieved from the respective Study Data Tabulation Model ([SDTM] dataset (SDTM.DV.DVCAT). 
No further protocol deviations are programmed in the analysis datasets for ADDV (if not otherwise 
specified in the SAP).
20.1.3
Demographics and other baseline characteristics
20.1.3.1
Subject demographics
Derivation of age
Age as provided in SDTM.DM.AGE will be used.
Derivation of BMI:
BMI is calculated to 1 decimal place using the following formula:
BMI [KG/M²] = WEIGHT [KG] / HEIGHT²[M]
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Derivation of race:
If for race more than 1 entry per subject is documented, a category “multiple” will be created.
20.1.3.2
Other baseline characteristics 
Not applicable.
20.1.3.3
Medical history 
For CRPS history, time since precipitating event, duration (time since onset of symptoms), and time 
since diagnosis 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 to 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.
Examples:
Missing date
Imputed date
2016-Mar
2016-Mar-01
2016
2016-Jan-01
20.1.3.4
Prior and concomitant medication or therapy
Prior and concomitant medication is collected as of enrollment in the eCRF 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.
Prerequisite is a complete date/time of first dose of IMP (entered or imputed). For subjects not 
allocated to treatment, the date/time of first IMP is not defined, and no prior or concomitant status 
will be assigned to their medications or therapies.
Stop of medication
or therapy
Date/time
Condition
Category
Complete date/time is 
available
Stop date/time is earlier than date/time 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
Missing hours
Day/month/year of stop date are earlier than day/month/year of first dose 
of IMP
Prior
Missing minutes
Day/month/year/hours of stop date/time are earlier than 
day/month/year/hours of first dose of IMP
Prior
Otherwise
Concomitant
Medication ticked in the eCRF as “continuing” will be classified as concomitant.
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The following rules are used to identify medications or therapies which started after last dose of 
IMP.
Prerequisite is a complete date/time of last dose of IMP (entered or imputed).
Start of medication or 
therapy
date/time
Condition
Start after last 
dose of IMP
Complete date/time is 
available
Start date/time is later than date/time of last dose of IMP
Yes
Complete date is available
Start date is later than or equal to date of last dose of IMP
Yes
Missing month
Year of start date is later than year of last dose of IMP
Yes
Missing day
Month/year of start date are later than month/year of last dose of 
IMP
Yes
Missing hours
Day/month/year of start date are later than day/month/year of last 
dose of IMP
Yes
Missing minutes
Day/month/year/hours of start date/time are later than 
day/month/year/hours of last dose of IMP
Yes
Otherwise
No
20.1.4
Efficacy analysis
There are no trial-specific definitions for this trial.
20.1.5
Analysis of pharmacokinetic and pharmacodynamic parameters
There are no trial-specific definitions for this trial.
20.1.6
Safety analysis
20.1.6.1
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 the 
Analysis of Data Model (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. 
If the number of adverse events with missing date information does not exceed 10% the following 
imputation strategy is applied.
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
Figure 2:
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.
•
Imputation:
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Incomplete
AE Start Date 
C1) Can AE start date
clearly be assessed as
after / before first IMP based on
partial date
C2) Can AE stop date
clearly be assessed as before
first IMP based on available
date information
12) Impute AE Start Date with:
a) first calendar day and /or
Yes—) 
first calendar month
b) first hour and/or first minute (if
applicable)
 Yes
C3) Imputed date
before date of informed
consent signed?
Imputed date is used
11)Impute AE Start Date with:
date of first IMP
C 
Step 1
Yes
13)Impute with:
date of informed
consent signed
/ Incomplete
/ AE Stop Date
C4) AE stop
date complete
missing?
 Yes
C 
Step 2 C
 ► 
No imputation
14) Impute AE Stop Date with:
 ►a) last calendar day and /or last calendar month
b) last hour and/or last minute (if applicable)


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−
I1: Impute with date/time of first IMP
−
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 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 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 first IMP.
−
C3: The decision must to be taken based on the available information (date/time) before 
imputation.
−
C4: The decision must to 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
Not applicable.
List of deaths
Death will be identified by outcome of adverse event equals “fatal”. 
Time to onset of adverse event
Time to onset of adverse event will be calculated based on first administration of IMP based on the 
imputed value for adverse event start date/time. 
Duration of adverse event
Duration of adverse event will be calculated based on the imputed values for adverse event start 
date/time and stop date/time. 
If duration of 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 eCRF, the duration will be categorized 
as “continuing”
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•
Otherwise the duration category will be set to “missing”.
Presentation of causal relationship
Causal relationship is ordered in descending order starting with the worst expression:
Expression
certain – probable/likely – possible – conditional/unclassified – unassessable/unclassifiable –
unlikely – not related
Subject experiencing a non-serious TEAEs
All subjects who had at least 1 non-serious TEAE will be taken into account independent of the 
experience of a serious TEAE. 
Exposure adjusted incidence rate
In case of missing dates, the imputed dates will be used for calculation of the total exposure time. If
the total exposure time equals 0 (thus all TEAEs start with first IMP administration), the total 
exposure time will be set to 0.1.
20.1.6.2
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 and the additional level “Missing”, 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 vs. 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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Values out of range
For some laboratory parameters, categories such as “positive” and “negative” will be used. The 
positive category could be further classified as positive “+” or borderline positive “(+)”.
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, 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-baseline 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.
20.2
List of statistical output documentation
The complete SAS output of the MMRM analysis of current, average, and worst pain intensities 
will be included in ICTR Section 16.1.9.
20.3
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.
20.3.1
Reference ranges for vital signs
The reference ranges for vital signs are defined in Table 7.
Table 7: 
Reference ranges for vital sign 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; LLN = lower limit of normal; mmHg = millimeter of mercury; ULN = upper limit of normal.
20.3.2
Sponsor-defined alert ranges for vital signs
The following table defines the sponsor-defined alert ranges for those vital sign parameters where 
lower or upper limits are specified.
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Table 8: 
Sponsor-defined alert ranges for vital sign 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.
20.3.3
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 9: 
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
QTcB interval
<300 msec
>480 msec
QTcF interval
<300 msec
>480 msec
bpm = beats per minute; ECG = electrocardiogram; QTcB = corrected QT interval (according to Bazett’s formula); 
QTcF = corrected QT interval (according to Fridericia’s formula).
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