Efficacy and Safety of Intravenous Neridronic Acid in CRPS

• Sponsor: Grünenthal GmbH (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03530345
• Collaborator: (none)
• Enrollment: 182
• Locations: 71
• Arms: 2
• Actual Duration (Months): 14
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

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

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

Condition or Disease	Intervention/Treatment	Phase
Complex Regional Pain Syndrome (CRPS)	Drug: Neridronic acid 100 mg; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Blinded treatment in Treatment Period A, open-label infusion in Treatment Period B.
• Primary Purpose: Treatment
• Official Title: Randomized, Double-blind, Placebo-controlled Trial Investigating the Efficacy and Safety of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome (CRPS)
• Actual Study Start Date: May 30, 2018
• Actual Primary Completion Date: Jul 31, 2019
• Actual Study Completion Date: Jul 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neridronic acid Neridronic acid 100 mg - 4 intravenous (i.v.) infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The investigational medicinal product (IMP) was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration. The maximum neridronic acid dose was 800 mg: 400 mg in Treatment Period A and 400 mg in Treatment Period B.	Drug: Neridronic acid 100 mg; 100 mg neridronic acid supplied in glass vials in 8 mL of excipients.
Placebo Comparator: Placebo Matching placebo - 4 intravenous infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The IMP was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration.	Drug: Placebo; Glass vials with matching placebo.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary) [From the Baseline Phase (Day -7 to Day -1) to Week 12]

   In the Baseline Phase and in Treatment Period A/Follow-up Period 1, participants were asked to assessed their average CRPS-related pain on an 11-point numerical rating scale (NRS) - from 0 = "no pain" to 10 = "pain as bad as you can imagine" and report it once daily (in the evening, 24-hour recall) in an electronic diary. Changes from baseline (average for the Baseline Phase) to the weekly average for Week 12 were calculated.

Secondary Outcome Measures

1. Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer. [From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)]

   11-point NRS - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported at the visits on a tablet computer (24-hour recall). Changes from baseline to Week 26 were planned to be analyzed.

2. Pain Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Average Pain Intensity at Week 12, Recorded on the Tablet Computer. [From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)]

   11-point NRS - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported at the visits on a tablet computer (24-hour recall). The number of participants with response at Week 12 was planned to be determined.

3. Pain Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Average Pain Intensity at Week 26, Recorded on the Tablet Computer. [From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)]

   11-point NRS - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported at the visits on a tablet computer (24-hour recall). The number of participants with response at Week 26 was planned to be determined.

4. Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA). [From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)]

   Dynamic mechanical allodynia: a tactile stimulus is applied in a single sweeping motion (1 cm to 2 cm length) on the skin on the affected limb. The participants are asked to judge the stimulus intensity by means of an NRS (0 to 10). "0" in this case means "no pain". Each "pricking", "stinging" or "burning" sensation is defined as a painful sensation, which should always be evaluated by giving a value greater than "0". "10" corresponds to the individual maximum pain imaginable. Change from baseline was planned to analyzed.

5. Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle. [From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)]

   Pressure pain threshold: using a pressure algometer (contact area 1 cm2), the threshold for pressure-induced pain is measured on the thenar muscle/abductor hallucis muscle in 3 series of slowly increasing stimulus intensities (at a rate of about 50 kPa/s). The threshold is then determined as the arithmetic mean of the 3 series (in kPa). The ratio of the thresholds of the affected limb versus the unaffected limb was planned to be calculated.

6. Change From Baseline to Week 12 in the Ratio of the Figure of Eight Measurements of the Affected Limb Versus the Unaffected Limb. [From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)]

   In participants with the CRPS sign of edema on the CRPS severity score at baseline, circumference of the hand or foot will be measured by the investigator with measurement tape using the figure-of-eight method at both the affected limb and the contralateral unaffected limb. Each measurement will be performed 3 times. The average of the 3 measurements will be used for further analysis. The ratio of the averages of the affected limb versus the unaffected limb was planned to be calculated and used for the determination of the change from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent signed.

• Male or female participant at least 18 years of age at Visit 1.

• A diagnosis of CRPS according to the clinical diagnostic criteria recommended by the International Association for the Study of Pain (IASP; "Budapest clinical criteria"), assessed at Visit 1. Signs and symptoms of CRPS must apply to an affected limb (arm or leg) and must demonstrate asymmetry with respect to the contralateral limb. The CRPS duration must be 2 years or less since onset of symptoms.

• A baseline average pain intensity score of greater than or equal to 4 using an 11-point numerical rating scale (NRS), referring to the CRPS-affected limb (average of pain recorded over 7 days). The baseline average pain intensity score will be calculated automatically by the electronic diary, which must be checked prior to allocation at Visit 2. A participant who has not met average baseline pain intensity requirements (at least 4 average pain intensity ratings) due to lack of compliance with the electronic diary may be rescheduled for Visit 2 (1 time only), with appropriate re-training to ensure compliance with use of the electronic diary.

• In stable treatment and follow-up therapy for CRPS for at least 1 month prior to allocation to treatment (Visit 2). Participants must have failed attempts with at least 2 available treatments for CRPS, 1 of which must have been a pharmacologic treatment.

• Women of child-bearing potential must have a negative urine Beta-human chorionic gonadotropin (ß-HCG) pregnancy test at Visit 1 and must be using 2 forms of medically acceptable contraception, including at least 1 highly effective method of contraception with a low failure rate, defined as less than 1% per year, 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.

• Participants must be able to communicate meaningfully, be able to differentiate with regard to location and intensity of the pain, and be able to answer the questions in the questionnaires used in this trial (assistance in filling out the questionnaires may be provided, if required due to motor or other physical impairment).

Exclusion Criteria:

• Evidence of severe renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73 m2 using the 2009 Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine equation [Levey et al. 2009] or a urinary albumin to creatinine ratio [ACR] greater than 150 mg/g), based on central safety laboratory data obtained prior to Visit 2. Note: a single repeat laboratory test is allowed.

• Serum calcium or magnesium outside of the central laboratory's reference range, based on central safety laboratory data obtained prior to Visit 2 (2 repeat laboratory tests are allowed); a history of hypocalcemia or a metabolic disorder anticipated to increase risk for hypocalcemia (e.g., hypoparathyroidism); anticipated need for any new drug with known potential to cause hypocalcemia (e.g., aminoglycosides, new treatment with or dose adjustment of loop diuretics) during the trial. Participants on a stable dose of loop diuretics may receive treatment with IMP as long as no dosage increases in the diuretic medication are anticipated and calcium levels are in the reference range.

• Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL (75 nmol/L), based on central safety laboratory data obtained prior to Visit 2 (up to 4 repeat laboratory tests are allowed). Participants with vitamin D deficiency should receive appropriate supplementation during the Enrollment Period. A vitamin D level of at least 30 ng/mL (75 nmol/L) must be documented prior to allocation to IMP.

• Corrected QT interval (according to Fridericia's formula; QTcF) greater than 470 ms (average of 3 Electrocardiogram (ECGs) obtained at Visit 1) according to central ECG reading facility evaluation or QTcF greater than 470 ms at pre-dose ECG at Visit 2 according to the investigator's judgment; serum potassium outside the central laboratory's reference range at Visit 1(a single repeat laboratory test is allowed); clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or an indwelling pacemaker; evidence of complete left bundle branch block; complete atrioventricular block; history of Long QT Syndrome or a relative with this condition; or any history of or other known risk factor for torsade de pointes.

• Participants receiving medications with a known risk of torsades de pointes within 7 days prior to allocation. Participants receiving selective serotonin re-uptake inhibitor antidepressants (e.g., citalopram, escitalopram) are eligible if the QT interval values do not meet the exclusion criteria, the medication was started at least 1 month prior to Visit 1, the dose is stable, and the dose is anticipated to remain stable throughout the trial.

• Any prior use of a bisphosphonate for treatment of CRPS, any prior administration of a bisphosphonate within the previous year, anticipated requirement for treatment with a bisphosphonate for another condition such as osteoporosis during the trial, or administration of denosumab (Prolia®) or other bone turnover suppressing drugs within 6 months prior to Visit 1.

• History of any allergic or hypersensitivity reaction to neridronic acid or other bisphosphonate, acetaminophen, or to vitamin D or calcium supplements.

• 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 that may pre-dispose to need for tooth extraction or other invasive dental procedures during the trial. Participants with indeterminate, suspicious or unreliable dental history, in the opinion of the investigator, must undergo a dental examination prior to receiving treatment.

• Evidence of denture-related gum trauma or improperly fitting dentures causing injury.

• Prior radiation therapy of the head or neck (within 1 year of Visit 1).

• History of malignancy within 2 years prior to Visit 1, with the exception of basal cell carcinoma.

• 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.

• Evidence of current alcohol or drug abuse, or history of alcohol or drug abuse within 2 years of Visit 1, based on participant history and physical examination and according to the investigator's judgment.

• 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 participants safety during trial participation.

• Women who are pregnant or breastfeeding.

• Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-fold upper limit of normal, based on central safety laboratory data obtained at Visit 1, or current evidence of chronic liver disease. Safety laboratory testing may be repeated prior to Visit 2, and participants will be allowed in the trial if results of 2 consecutive tests, at least 3 days apart, are less than or equal to 2-fold upper limit of normal.

• Participation in another investigational drug trial within 3 months prior to Visit 1, or any previous trial involving neridronic acid.

• Participant 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.

• Participants taking forbidden concomitant medications/therapies or not being able to follow the rules of use of concomitant treatment.

• Participants incapable of giving informed consent.

Criteria to continue into Treatment Period B

• A value of at least 4 on the pain intensity question (question number 29, GLOBAL07) of the Patient-Reported Outcomes Measurement Information System (PROMIS®) (PROMIS-29 profile) at Visit 11.

The following exclusion criteria are not met:

• Evidence of severe renal impairment (eGFR less than 30 mL/min/1.73 m2 using the 2009 CKD-EPI creatinine equation [Levey et al. 2009] or a urinary ACR greater than 150 mg/g), based on central safety laboratory data obtained prior to Visit 11. A single repeat laboratory test is allowed.

• Corrected QT interval (QTcF) greater than 470 ms (average of 3 ECGs obtained at Visit

1. according to the central ECG reading facility evaluation or QTcF greater than 470 ms at pre-dose ECG at Visit 11 according to the investigator's judgment; serum potassium outside the central laboratory's reference range at Visit 10 (a single repeat laboratory test is allowed); clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or an indwelling pacemaker; evidence of complete left bundle branch block; complete atrioventricular block; any other known risk factor for torsade de pointes.

• Participants receiving medications with a known risk of torsades de pointes within 7 days prior to re-allocation.

• Participants taking forbidden concomitant medications/therapies or not being able to follow the rules of use of concomitant treatment.

• Recent tooth extraction or other invasive dental procedure (within 3 months prior to Visit 11), unhealed or infected extraction site, or significant dental/periodontal disease that may pre-dispose to need for tooth extraction or other invasive dental procedures during the further course of the trial.

• Serum calcium or magnesium outside of the central laboratory's reference range, despite appropriate supplementation between Visit 10 and Visit 11, based on the last central safety laboratory data obtained prior to Visit 11. One repeat laboratory test is allowed.

• Vitamin D deficiency prior to IMP re-allocation, defined as a 25(OH)D level less than 30 ng/mL (75 nmol/L), based on the last central safety laboratory data obtained prior to Visit 11, i.e., inability to normalize 25(OH)D levels to at least 30 ng/mL (75 nmol/L) despite appropriate supplementation between Visit 10 and Visit 11. Two repeat laboratory tests are allowed (with a minimum interval of 3 days).

• Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-fold upper limit of normal, based on central safety laboratory data obtained at Visit 10, or current evidence of chronic liver disease. A single repeat laboratory test is allowed.

• No other criterion for trial and/or IMP discontinuation is met.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	US015 - Tennessee Valley Pain Consultants	Huntsville	Alabama	United States	35801
2	US043 - Horizon Research Partners	Mobile	Alabama	United States	36605
3	US045 - Holland Center for Family Health	Peoria	Arizona	United States	85381
4	US003 - HealthStar Research	Hot Springs	Arkansas	United States	71913
5	US049 - Orange County Research Institute	Anaheim	California	United States	92801
6	US053 - Core Healthcare Group	Cerritos	California	United States	90703
7	US013 - Inland Pain Medicine	Colton	California	United States	92324
8	US044 - The Helm Center for Pain Management	Laguna Woods	California	United States	92637
9	US052 - Providere' Research Inc.	West Covina	California	United States	91790
10	US036 - Denver Back Pain Specialists	Greenwood Village	Colorado	United States	80111
11	US007 - Neurology Offices of South Florida	Boca Raton	Florida	United States	33428
12	US030 - Gulfcoast Clinical Research Center	Fort Myers	Florida	United States	33912
13	US004 - The Chappel Group Research	Kissimmee	Florida	United States	34744
14	US023 - AGR Research	Lake Worth	Florida	United States	33462
15	US020 - SIMEDHealth	Ocala	Florida	United States	34474
16	US012 - NeuroMedical Research Center	Panama City	Florida	United States	32405
17	US046 - Clinical Research of West Florida, Inc.	Tampa	Florida	United States	33603
18	US027 - Drug Studies America	Marietta	Georgia	United States	30060
19	US041 - Better Health Clinical Research, Inc.	Newnan	Georgia	United States	30265
20	US032 - Millennium Pain Center	Bloomington	Illinois	United States	61704
21	US011 - Otrimed Corporation	Edgewood	Kentucky	United States	41017
22	US040 - Regeneris Medical	North Attleboro	Massachusetts	United States	02760
23	Us054 - Aa Mrc	Flint	Michigan	United States	48504
24	US025 - Oakland Medical Research	Troy	Michigan	United States	48085
25	US009 - Elite Clinical Research	Jackson	Mississippi	United States	39202
26	US017 - Jackson Anesthesia Pain Center	Jackson	Mississippi	United States	39202
27	US033 - Galen Research	Chesterfield	Missouri	United States	63005
28	US050 - Premier Pain Centers	Shrewsbury	New Jersey	United States	07702
29	US029 - Dent Neurologic Institute	Amherst	New York	United States	14226
30	US038 - DiGiovanna Institute For Medical Education	North Massapequa	New York	United States	11758
31	US022 - The Neurological Institute	Charlotte	North Carolina	United States	28204
32	US047 - The Center for Clinical Research	Winston-Salem	North Carolina	United States	27103
33	US005 - Hometown Urgent Care and Research	Dayton	Ohio	United States	45424
34	US021 - SP Research PLLC	Oklahoma City	Oklahoma	United States	73112
35	US028 - Founders Research Corporation	Philadelphia	Pennsylvania	United States	19152
36	US018 - Carolinas Center for Advanced Management of Pain	Spartanburg	South Carolina	United States	29303
37	US055 - Diversified Medical Practices	Houston	Texas	United States	77057
38	US048 - Axios Research	Salt Lake City	Utah	United States	84106
39	US037 - Clinical Research Partners	Richmond	Virginia	United States	23235
40	AU002 - Royal North Shore Hospital Michael J Cousins Pain Management and Research Centre	St Leonards	New South Wales	Australia	2065
41	AU005 - Port Kembla Public Hospital	Wollongong	New South Wales	Australia	2502
42	AU003 - Neuro Trials Victoria Pty Ltd	Noble Park	Victoria	Australia	3174
43	AU001 - The Avenue Cardiovascular Centre Level 1 Masada Private Hospital	St Kilda East	Victoria	Australia	3183
44	FR004 - Centre Hospitalier Universitaire Amiens Picardie	Amiens Cedex 1		France	80054
45	FR001 - Centre Hospitalier Universitaire Grenoble Alpes Centre de la douleur	Grenoble		France	38043
46	FR002 - L'Hôpital Privé du Confluent Département d'évaluation et traitement de la douleur	Nantes Cedex 2		France	44277
47	DE006 - Center for Clinical Research Dr. med. I. Schoel	Bad Homburg		Germany	61348
48	DE011 - Klinische Forschung Berlin Mitte GmbH	Berlin		Germany	10117
49	DE009 - BAG Anästhesie, Schmerztherapie, Palliativmedizin	Cottbus		Germany	03046
50	DE002 - Klinische Forschung Hamburg GmbH	Hamburg		Germany	20253
51	DE010 - Klinische Forschung Hannover Mitte	Hannover		Germany	30159
52	DE013 - Klinik und Poliklinik für Neurologie Universitätsmedizin Mainz	Mainz		Germany	55131
53	DE005 - Klinische Forschung Schwerin GmbH	Schwerin		Germany	19055
54	KR008 - Chungnam National University Hospital	Daejeon		Korea, Republic of	35015
55	KR003 - Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of	13620
56	KR002 - Seoul National University Hospital	Seoul		Korea, Republic of	03080
57	KR005 - Samsung Medical Center	Seoul		Korea, Republic of	06351
58	KR007 - Konkuk University Medical Center	Seoul		Korea, Republic of	5030
59	KR004 - Seoul St Mary's Hospital	Seoul		Korea, Republic of	6591
60	KR006 - Korea University Guro Hospital	Seoul		Korea, Republic of	8308
61	KR001 - Ajou University Medical Center	Suwon		Korea, Republic of	16499
62	NZ004 - Optimal Clinical Trials	Grafton	Auckland	New Zealand	1010
63	Nz001 - Bay of Plenty Clinical Trials Unit, Bay of Plenty District Health Board	Tauranga	BAY OF Plenty	New Zealand	3112
64	NZ002 - Southern Clinical Trials Group Ltd	Christchurch	Canterbury	New Zealand	8013
65	ES009 - General Hospital of Alicante	Alicante		Spain	03010
66	ES002 - Hospital de la Santa Creu i Sant Pau	Barcelona		Spain	08041
67	ES005 - Hospital Sanitas La Moraleja Pain Unit	Madrid		Spain	28050
68	ES004 - Hospital Universitario Puerto Real Unidad de Anestesiologia	Puerto Real		Spain	11510
69	ES006 - Hospital Infanta Luisa Rheumatology	Sevilla		Spain	41010
70	ES007 - Hospital Clínico Universitario de Valencia	Valencia		Spain	46010
71	ES008 - Hospital Lluis Alcanyis Anesthesiology and Pain Unit	Xativa		Spain	46800

Sponsors and Collaborators

• Grünenthal GmbH

Investigators

• Study Director: Grünenthal Study Director, Grünenthal GmbH

Study Documents (Full-Text)

• Statistical Analysis Plan: Pooled-Interim-Analysis-KF7013-02-KF7013-04 - Jul 3, 2018
• Study Protocol - Nov 20, 2018
• Statistical Analysis Plan: Final-Analysis-KF7013-02 - Jun 10, 2018

More Information

Publications

• Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. Erratum in: Ann Intern Med. 2011 Sep 20;155(6):408.

• Responsible Party: Grünenthal GmbH
• ClinicalTrials.gov Identifier: NCT03530345
• Other Study ID Numbers: KF7013-02; 2016-003833-91; U1111-1187-8036
• First Posted: May 21, 2018
• Last Update Posted: Aug 6, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Grünenthal GmbH: Neridronic Acid; Neridronate; CRPS; reflex sympathetic dystrophy (RSD)
• Additional relevant MeSH terms: Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy; Syndrome

Study Results

Participant Flow

Recruitment Details	First participant enrollment on 30 May 2018. After a pooled interim analysis of primary endpoint data of studies KF7013-02 and KF7013-04 (NCT03560986), recruitment was stopped as interim results indicated futility. Last participant's last assessment was on 31 July 2019.
Pre-assignment Detail	182 participants were enrolled (signed consent), 57 were allocated to treatment and received study medication. Of 125 participants not allocated, 95 did not meet inclusion/met exclusion criteria, 1 was lost to follow-up, 9 withdrew consent, 1 experienced technical problems, and 19 were not allocated for other reasons.

Arm/Group Title	Neridronic Acid - Treatment Period A/B	Placebo - Treatment Period A/B
Arm/Group Description	Treatment Period A: Neridronic acid 100 mg - 4 intravenous infusions within 10 days; Follow-up Period 1 until 26 weeks. Treatment Period B: Neridronic acid 100 mg - 4 intravenous infusions within 10 days; Follow-up Period 2 until 52 weeks.	Treatment Period A: Matching placebo - 4 intravenous infusions within 10 days; Follow-up Period 1 until 26 weeks. Treatment Period B: Neridronic acid 100 mg - 4 intravenous infusions within 10 days; Follow-up Period 2 until 52 weeks.
Period Title: Treatment Period A/Follow-up Period 1
STARTED	28	29
Treatment Period A Completers	26	27
COMPLETED	7	7
NOT COMPLETED	21	22
Period Title: Treatment Period A/Follow-up Period 1
STARTED	5	7
Treatment Period B Completers	4	6
COMPLETED	0	0
NOT COMPLETED	5	7

Baseline Characteristics

Arm/Group Title	Neridronic Acid - Treatment Period A	Placebo - Treatment Period A	Total
Arm/Group Description	Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days in Treatment Period A.	Matching placebo administered by 4 intravenous infusions within 10 Days in Treatment Period A.	Total of all reporting groups
Overall Participants	28	29	57
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.1 (11.0)	49.4 (12.1)	47.8 (11.6)
Age, Customized (Count of Participants)
< 18 years	0 0%	0 0%	0 0%
From 18 to <65 years	28 100%	25 86.2%	53 93%
From 65 to <85 years	0 0%	4 13.8%	4 7%
85 years and above	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	22 78.6%	22 75.9%	44 77.2%
Male	6 21.4%	7 24.1%	13 22.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 7.1%	0 0%	2 3.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 7.1%	1 3.4%	3 5.3%
White	24 85.7%	28 96.6%	52 91.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
New Zealand	0 0%	1 3.4%	1 1.8%
South Korea	2 7.1%	0 0%	2 3.5%
United States	22 78.6%	22 75.9%	44 77.2%
Australia	0 0%	1 3.4%	1 1.8%
Germany	1 3.6%	0 0%	1 1.8%
Spain	3 10.7%	5 17.2%	8 14%
Complex regional pain syndrome (CRPS) type (Count of Participants)
CRPS Type I	25 89.3%	21 72.4%	46 80.7%
CRPS Type II	3 10.7%	8 27.6%	11 19.3%
Time since onset of CRPS symptoms (months) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [months]	17.72	13.47	14.23
Time since diagnosis of CRPS (months) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [months]	9.15	11.37	10.37

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary)
Description	In the Baseline Phase and in Treatment Period A/Follow-up Period 1, participants were asked to assessed their average CRPS-related pain on an 11-point numerical rating scale (NRS) - from 0 = "no pain" to 10 = "pain as bad as you can imagine" and report it once daily (in the evening, 24-hour recall) in an electronic diary. Changes from baseline (average for the Baseline Phase) to the weekly average for Week 12 were calculated.
Time Frame	From the Baseline Phase (Day -7 to Day -1) to Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set; all participants treated in Treatment Period A with all data available at the time of last participant out following premature study termination.

Arm/Group Title	Neridronic Acid - Treatment Period A	Placebo - Treatment Period A
Arm/Group Description	Neridronic acid 100 mg - 4 intravenous infusions within 10 Days	Matching placebo - 4 intravenous infusions within 10 Days
Measure Participants	28	29
Least Squares Mean (Standard Error) [units on a scale]	-1.23 (0.310)	-0.16 (0.305)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Neridronic Acid - Treatment Period A, Placebo - Treatment Period A
	Comments	Mixed-effects model for repeated measures (MMRM) defined with baseline pain intensity as covariate, the factors geographic region, week, treatment and treatment-by-week as fixed effects, and an unstructured covariance matrix to model the covariance structure of the repeated measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0111
	Comments	2-sided p-value for testing superiority of neridronic acid 400 mg compared to placebo.
	Method	Mixed Models Analysis
	Comments	The degrees of freedom of the denominator are estimated using the Kenward-Roger approximation.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.07
	Confidence Interval	(2-Sided) 95%; -1.89 to -0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.404
	Estimation Comments	The primary endpoint estimate was the least squares mean differences of change from baseline in pain NRS (electronic diary) at Week 12 between neridronate and Placebo.

2. Secondary Outcome

Title	Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer.
Description	11-point NRS - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported at the visits on a tablet computer (24-hour recall). Changes from baseline to Week 26 were planned to be analyzed.
Time Frame	From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)

Outcome Measure Data

Analysis Population Description

Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.

Arm/Group Title	Neridronic Acid - Treatment Period A	Placebo - Treatment Period A
Arm/Group Description	Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days in Treatment Period A.	Matching placebo administered by 4 intravenous infusions within 10 Days in Treatment Period A.
Measure Participants	0	0

3. Secondary Outcome

Title	Pain Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Average Pain Intensity at Week 12, Recorded on the Tablet Computer.
Description	11-point NRS - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported at the visits on a tablet computer (24-hour recall). The number of participants with response at Week 12 was planned to be determined.
Time Frame	From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)

Outcome Measure Data

Analysis Population Description

Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.

Arm/Group Title	Neridronic Acid - Treatment Period A	Placebo - Treatment Period A
Arm/Group Description	Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days in Treatment Period A.	Matching placebo administered by 4 intravenous infusions within 10 Days in Treatment Period A.
Measure Participants	0	0

4. Secondary Outcome

Title	Pain Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Average Pain Intensity at Week 26, Recorded on the Tablet Computer.
Description	11-point NRS - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported at the visits on a tablet computer (24-hour recall). The number of participants with response at Week 26 was planned to be determined.
Time Frame	From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)

Outcome Measure Data

Analysis Population Description

Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.

Arm/Group Title	Neridronic Acid - Treatment Period A	Placebo - Treatment Period A
Arm/Group Description	Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days in Treatment Period A.	Matching placebo administered by 4 intravenous infusions within 10 Days in Treatment Period A.
Measure Participants	0	0

5. Secondary Outcome

Title	Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA).
Description	Dynamic mechanical allodynia: a tactile stimulus is applied in a single sweeping motion (1 cm to 2 cm length) on the skin on the affected limb. The participants are asked to judge the stimulus intensity by means of an NRS (0 to 10). "0" in this case means "no pain". Each "pricking", "stinging" or "burning" sensation is defined as a painful sensation, which should always be evaluated by giving a value greater than "0". "10" corresponds to the individual maximum pain imaginable. Change from baseline was planned to analyzed.
Time Frame	From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)

Outcome Measure Data

Analysis Population Description

Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.

Arm/Group Title	Neridronic Acid - Treatment Period A	Placebo - Treatment Period A
Arm/Group Description	Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days in Treatment Period A.	Matching placebo administered by 4 intravenous infusions within 10 Days in Treatment Period A.
Measure Participants	0	0

6. Secondary Outcome

Title	Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle.
Description	Pressure pain threshold: using a pressure algometer (contact area 1 cm2), the threshold for pressure-induced pain is measured on the thenar muscle/abductor hallucis muscle in 3 series of slowly increasing stimulus intensities (at a rate of about 50 kPa/s). The threshold is then determined as the arithmetic mean of the 3 series (in kPa). The ratio of the thresholds of the affected limb versus the unaffected limb was planned to be calculated.
Time Frame	From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)

Outcome Measure Data

Analysis Population Description

Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.

Arm/Group Title	Neridronic Acid - Treatment Period A	Placebo - Treatment Period A
Arm/Group Description	Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days in Treatment Period A.	Matching placebo administered by 4 intravenous infusions within 10 Days in Treatment Period A.
Measure Participants	0	0

7. Secondary Outcome

Title	Change From Baseline to Week 12 in the Ratio of the Figure of Eight Measurements of the Affected Limb Versus the Unaffected Limb.
Description	In participants with the CRPS sign of edema on the CRPS severity score at baseline, circumference of the hand or foot will be measured by the investigator with measurement tape using the figure-of-eight method at both the affected limb and the contralateral unaffected limb. Each measurement will be performed 3 times. The average of the 3 measurements will be used for further analysis. The ratio of the averages of the affected limb versus the unaffected limb was planned to be calculated and used for the determination of the change from baseline.
Time Frame	From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)

Outcome Measure Data

Analysis Population Description

Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.

Arm/Group Title	Neridronic Acid - Treatment Period A	Placebo - Treatment Period A
Arm/Group Description	Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days in Treatment Period A.	Matching placebo administered by 4 intravenous infusions within 10 Days in Treatment Period A.
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events were documented from the time of enrollment (i.e., the time the informed consent form was signed) up to the time of the last protocol scheduled contact, i.e., date of last visit/contact (could be a phone call, e.g., in case of withdrawal). Only treatment emergent adverse events (TEAEs, i.e., those reported from baseline (after first administration of study medication) are reported in the tables below.
Adverse Event Reporting Description	Participants with TEAEs may be presented in 2 of 6 reporting groups depending on the time the TEAEs were reported. Treatment Period A/Follow-up Period 1 (TPA): Baseline to Week 26 (Placebo or neridronic acid). Treatment Period B/Follow-up Period 2 (TPB): Week 26 to Week 52 (follow-up without study medication administration) or Week 26 to Week 52 (participants with neridronic acid treatment after placebo and those receiving re-treatment with neridronic acid).
Arm/Group Title	Baseline to Week 26: Placebo TPA		Baseline to Week 26: Neridronic Acid TPA		Week 26 to Week 52: Placebo TPA		Week 26 to Week 52: Placebo TPA, Neridronic Acid TPB		Week 26 to Week 52: Neridronic Acid TPA		Week 26 to Week 52: Neridronic Acid TPA, Neridronic Acid TPB
Arm/Group Description	In Treatment Period A, participants received matching placebo - 4 intravenous infusions within 10 Days; Follow-up Period 1 until 26 weeks.		In Treatment Period A, participants received neridronic acid 100 mg - 4 intravenous infusions within 10 days; Follow-up Period 1 until 26 weeks.		Participants with placebo treatment in Treatment Period A/Follow-up Period 1 were followed up without administration of study medication until 52 weeks in Follow-up Period 2.		Participants who had completed treatment with placebo in Treatment Period A/Follow-up Period 1 received neridronic acid treatment (100 mg - 4 intravenous infusions within 10 days) in Treatment Period B/Follow-up Period 2 until 52 weeks.		Participants who had completed treatment with neridronic acid treatment in Treatment Period A/Follow-up Period 1 were followed up without administration of study medication until 52 weeks in Follow-up Period 2.		Participants who had completed treatment with neridronic acid in Treatment Period A/Follow-up Period 1 received re-treatment with neridronic acid 100 mg - 4 intravenous infusions within 10 days; Follow-up Period 2 until 52 weeks.
All Cause Mortality
	Baseline to Week 26: Placebo TPA		Baseline to Week 26: Neridronic Acid TPA		Week 26 to Week 52: Placebo TPA		Week 26 to Week 52: Placebo TPA, Neridronic Acid TPB		Week 26 to Week 52: Neridronic Acid TPA		Week 26 to Week 52: Neridronic Acid TPA, Neridronic Acid TPB
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/28 (0%)		0/22 (0%)		0/7 (0%)		0/23 (0%)		0/5 (0%)
Serious Adverse Events
	Baseline to Week 26: Placebo TPA		Baseline to Week 26: Neridronic Acid TPA		Week 26 to Week 52: Placebo TPA		Week 26 to Week 52: Placebo TPA, Neridronic Acid TPB		Week 26 to Week 52: Neridronic Acid TPA		Week 26 to Week 52: Neridronic Acid TPA, Neridronic Acid TPB
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		2/28 (7.1%)		0/22 (0%)		0/7 (0%)		0/23 (0%)		0/5 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Psychiatric disorders
Suicidal ideation	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Other (Not Including Serious) Adverse Events
	Baseline to Week 26: Placebo TPA		Baseline to Week 26: Neridronic Acid TPA		Week 26 to Week 52: Placebo TPA		Week 26 to Week 52: Placebo TPA, Neridronic Acid TPB		Week 26 to Week 52: Neridronic Acid TPA		Week 26 to Week 52: Neridronic Acid TPA, Neridronic Acid TPB
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/29 (51.7%)		16/28 (57.1%)		0/22 (0%)		3/7 (42.9%)		1/23 (4.3%)		0/5 (0%)
Cardiac disorders
Atrial flutter	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Eye disorders
Dry eye	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Eye pain	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Abdominal pain upper	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Burning mouth syndrome	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Constipation	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Dental paraesthesia	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Diarrhoea	1/29 (3.4%)	1	2/28 (7.1%)	2	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Gastritis	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Gastrooesophageal reflux disease	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Gingival discomfort	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Nausea	4/29 (13.8%)	4	2/28 (7.1%)	2	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Vomiting	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
General disorders
Acute phase reaction	0/29 (0%)	0	4/28 (14.3%)	7	0/22 (0%)	0	3/7 (42.9%)	6	0/23 (0%)	0	0/5 (0%)	0
Chest pain	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Fatigue	2/29 (6.9%)	5	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Feeling cold	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Influenza like illness	2/29 (6.9%)	2	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Oedema peripheral	0/29 (0%)	0	2/28 (7.1%)	5	0/22 (0%)	0	1/7 (14.3%)	1	0/23 (0%)	0	0/5 (0%)	0
Pain	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Pyrexia	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Infections and infestations
Bronchitis	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Nasopharyngitis	0/29 (0%)	0	2/28 (7.1%)	2	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Pharyngitis streptococcal	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Sinusitis	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Urinary tract infection	0/29 (0%)	0	0/28 (0%)	0	0/22 (0%)	0	1/7 (14.3%)	1	0/23 (0%)	0	0/5 (0%)	0
Injury, poisoning and procedural complications
Epicondylitis	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Skin laceration	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Fall	0/29 (0%)	0	0/28 (0%)	0	0/22 (0%)	0	1/7 (14.3%)	1	0/23 (0%)	0	0/5 (0%)	0
Investigations
Aspartate aminotransferase increased	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Lipase increased	1/29 (3.4%)	2	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Metabolism and nutrition disorders
Hypercalcaemia	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/29 (3.4%)	2	0/28 (0%)	0	0/22 (0%)	0	1/7 (14.3%)	1	0/23 (0%)	0	0/5 (0%)	0
Joint instability	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Musculoskeletal pain	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Myalgia	0/29 (0%)	0	1/28 (3.6%)	2	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Pain in extremity	2/29 (6.9%)	2	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Periarthritis	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Synovitis	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Back pain	0/29 (0%)	0	0/28 (0%)	0	0/22 (0%)	0	1/7 (14.3%)	1	0/23 (0%)	0	0/5 (0%)	0
Nervous system disorders
Dizziness	0/29 (0%)	0	2/28 (7.1%)	2	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Headache	3/29 (10.3%)	6	2/28 (7.1%)	2	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Migraine	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Occipital neuralgia	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Paraesthesia	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Psychiatric disorders
Anxiety	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Depression	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Insomnia	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Renal and urinary disorders
Haematuria	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Pulmonary embolism	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Skin and subcutaneous tissue disorders
Blister	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Night sweats	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Pruritus	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Rash	1/29 (3.4%)	1	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Surgical and medical procedures
Foot operation	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Medical device removal	0/29 (0%)	0	1/28 (3.6%)	1	0/22 (0%)	0	0/7 (0%)	0	0/23 (0%)	0	0/5 (0%)	0
Medical device implantation	0/29 (0%)	0	0/28 (0%)	0	0/22 (0%)	0	0/7 (0%)	0	1/23 (4.3%)	1	0/5 (0%)	0

Limitations/Caveats

A pre-specified interim analysis was conducted on pooled primary endpoint data of studies KF7013-02 and KF7013-04 (NCT03560986). The interim analysis indicated futility (neridronate unlikely to be superior to placebo) and both studies were stopped.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor reserves the right to review any proposed full publication or poster or presentation of the results of this study by the coordinating or other investigator before they are submitted for publication or public disclosure. Neither the sponsor nor the coordinating investigator has the right to prohibit publication or public disclosure. Publication or public disclosure can be postponed for patent purposes.