Safety of Intravenous Neridronic Acid in CRPS

• Sponsor: Grünenthal GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02972359
• Collaborator: (none)
• Enrollment: 580
• Locations: 46
• Arm: 1
• Actual Duration (Months): 24.6
• Patients Per Site: 12.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Complex Regional Pain Syndrome	Drug: Neridronic acid	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 580 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label Safety Trial of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome (CRPS)
• Actual Study Start Date: Dec 20, 2016
• Actual Primary Completion Date: Jan 9, 2019
• Actual Study Completion Date: Jan 9, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neridronic acid 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.	Drug: Neridronic acid; Neridronic acid administered as intravenous infusion.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) [Day 1 to Week 52]

   The primary endpoint of this trial was a binary endpoint assessing whether or not a participant experienced any TEAE.

Secondary Outcome Measures

1. Number of Participants With Occurrence of Permanent Discontinuation From Treatment Due to an Adverse Event [Day 1 to Day 10]

   The investigator could choose to permanently discontinue a participant from treatment if continued exposure of the participant to neridronic acid could have posed an undue risk to the participant.

2. Change From Baseline in the Current Pain Intensity Score [Baseline to Week 12 and Week 26]

   The current Complex Regional Pain Syndrome (CRPS)-related pain intensity score was captured at each visit using an 11-point numerical rating scale where 0 = "no pain" and 10 = "pain as bad as you can imagine", a higher score indicates more pain.

3. Number of Participants With Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score [Baseline, at Week 12 and Week 26]

   Participants with at least a 30 percent decrease in the current pain intensity score were considered to have responded to treatment.

4. Number of Participants With Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score [Baseline, at Week 12 and Week 26]

   Participants with at least a 50 percent decrease in the current pain intensity score were considered to have responded to treatment.

5. Patient Global Impression of Change (PGIC) at Week 12 [at Week 12]

   The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from "very much improved" to "very much worse". A response of "very much improved" or "much improved" is generally regarded as a clinically important improvement.

6. Patient Global Impression of Change (PGIC) at Week 26 [at Week 26]

   The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from "very much improved" to "very much worse". A response of "very much improved" or "much improved" is generally regarded as a clinically important improvement.

7. Change in the Pain Interference Score of the Brief Pain Inventory (BPI) [Baseline to Week 12 and Week 26]

   The Brief Pain Inventory (BPI) Interference Score is the mean value of 7 self-reported items in question 9 of the BPI Short Form Questionnaire. Participants rated their interference of pain with general activity, walking, work, sleep and other activities in the past 24 hours, with possible ratings from 0 (does not interfere) to 10 (completely interferes). The BPI interference Score ranges from 0 to 10, with higher values indicating greater pain interference of daily activities.

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 complex regional pain syndrome 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.

• Ongoing moderate to severe chronic pain, including a baseline current pain intensity score of greater than or equal to 4 using an 11-point Numerical Rating Scale, referring to the CRPS-affected limb, at Visit 2 (prior to dosing).

• 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 trials of at least 2 treatments for CRPS, one of which must be a pharmacologic treatment.

• 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 less than 1% per year (e.g., oral contraceptives or intrauterine device), and a second medically acceptable method such as use of condoms with spermicide by their male partner. A barrier method alone is not acceptable. Highly effective methods of contraception must be used for at least 1 month prior to Visit 2 and for the duration of the trial.

• 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 impairment).

Exclusion Criteria:

• Evidence of renal impairment (estimated glomerular filtration rate [eGFR] less than 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 greater than 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.

• Serum calcium or magnesium outside of the central laboratory's reference range, based on central safety laboratory data obtained prior to Visit 2 (a single repeat laboratory test is allowed); 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).

• Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL, 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 must be documented prior to allocation to investigational medicinal product (IMP).

• Corrected QT interval (according to Fridericia's formula; QTcF) greater than 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.

• 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) 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.

• 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.

• 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 (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. 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 2.

• 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 participant's 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 with neridronic acid, with the exception of participants of KF7013-01 who were assigned to placebo and did not receive 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 signing the informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	US017: Cactus Clinical Research, Inc.	Phoenix	Arizona	United States	85012
2	US028: Quality of Life Medical and Research Centers LLC	Tucson	Arizona	United States	85712
3	US045: Woodland International Research Group	Little Rock	Arkansas	United States	72211
4	US044: Woodland Research Northwest	Rogers	Arkansas	United States	72758
5	US012: Orange County Research Institute	Anaheim	California	United States	92801
6	US022: Core Healthcare Group	Cerritos	California	United States	90703
7	US033: Alliance Research Centers	Laguna Hills	California	United States	92653
8	US027: The Helm Center for Pain Management	Laguna Woods	California	United States	92637
9	US003: Samaritan Center for Medical Research	Los Gatos	California	United States	95032
10	US010: Catalina Research Institute, LLC	Montclair	California	United States	91763
11	US014: Northern California Research	Sacramento	California	United States	95821
12	US034: Mountain View Clinical Research, Inc.	Denver	Colorado	United States	80209
13	US032: South Lake Pain Institute	Clermont	Florida	United States	34711
14	US001: Sunrise Research Institute, Inc	Miami	Florida	United States	33130
15	US046: AMPM Research Clinic	Miami	Florida	United States	33169
16	US035: Compass Research	Orlando	Florida	United States	32806
17	US031: Gold Coast Research, LLC	Plantation	Florida	United States	33317
18	US011: Clinical Research of West Florida, Inc.	Tampa	Florida	United States	33603
19	US040: Palm Beach Research Center	West Palm Beach	Florida	United States	33409
20	US026: Better Health Clinical Research Inc.	Newnan	Georgia	United States	30265
21	US004: Northwestern University - Feinberg School of Medicine - Rehabilitation Institute of Chicago (RIC)	Chicago	Illinois	United States	60611
22	US036: University Anesthesiologists, S.C.	Chicago	Illinois	United States	60612
23	US029: Great Lakes Clinical Trials LLC	Chicago	Illinois	United States	60640
24	US005: International Clinical Research Institute	Overland Park	Kansas	United States	66210
25	US037: St. Louis Clinical Trials, LC	Saint Louis	Missouri	United States	63141
26	US051: Creighton University, Osteoporosis Research Center	Omaha	Nebraska	United States	68122
27	US002: Princeton Medical Institute	Princeton	New Jersey	United States	08540
28	US049: Premier Pain Centers, LLC	Shrewsbury	New Jersey	United States	07702
29	US048: Albany Medical College	Albany	New York	United States	12208
30	US043: Translational Pain Research, University of Rochester	Rochester	New York	United States	14618
31	US009: The Center for Clinical Research, LLC	Winston-Salem	North Carolina	United States	27103
32	US016: North Star Medical Research, LLC	Middleburg Heights	Ohio	United States	44130
33	US007: Medical Research International	Oklahoma City	Oklahoma	United States	73109-4520
34	US006: Abington Neurological Associates, LTD.	Willow Grove	Pennsylvania	United States	19090
35	US020: Clinical Trials of South Carolina	Charleston	South Carolina	United States	29406
36	US038: Vanderbilt University Medical Center	Nashville	Tennessee	United States	37212-1050
37	US019: Austin Center for Clinical Research	Austin	Texas	United States	78758
38	US008: Pioneer Research Solutions	Houston	Texas	United States	77099
39	US023: Axios Research, LLC	Salt Lake City	Utah	United States	84106
40	US018: Washington Center for Pain Management	Bellevue	Washington	United States	98004
41	US015: Northwest Clinical Research Center	Bellevue	Washington	United States	98007
42	US013: Swedish Pain Services/ Research Institute	Seattle	Washington	United States	98122
43	DE001: Klinische Forschung Hannover-Mitte GmbH	Hannover		Germany	30159
44	DE004: Schmerzambulanz Medizinishe Hochschule Hannover	Hannover		Germany	30625
45	DE006: AmBeNet GmbH	Leipzig		Germany	04107
46	DE002: Schmerztagesklinik der Anästhesiologie Universitätsklinikum Würzburg	Würzburg		Germany	97080

Sponsors and Collaborators

• Grünenthal GmbH

Investigators

• Study Director: Study Director, Grünenthal GmbH

Study Documents (Full-Text)

• Study Protocol - Nov 17, 2017
• Statistical Analysis Plan - May 15, 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: NCT02972359
• Other Study ID Numbers: KF7013-03; 2016-001164-11; U1111-1180-8099
• First Posted: Nov 23, 2016
• Last Update Posted: Nov 21, 2019
• Last Verified: Nov 1, 2019

• 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; RSD (reflex sympathetic dystrophy)
• Additional relevant MeSH terms: Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy; Syndrome

Study Results

Participant Flow

Recruitment Details	The first participant was enrolled on 20 December 2016.
Pre-assignment Detail	A total of 580 participants signed an informed consent form, 318 participants hereof were allocated to treatment. Two of the allocated participants did not meet inclusion criteria/met exclusion criteria, thus 316 participants received treatment.

Arm/Group Title	Neridronic Acid
Arm/Group Description	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 as intravenous infusion.
Period Title: Overall Study
STARTED	318
COMPLETED	247
NOT COMPLETED	71

Baseline Characteristics

Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
Overall Participants	316
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	290 91.8%
>=65 years	26 8.2%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	47.4
Sex: Female, Male (Count of Participants)
Female	237 75%
Male	79 25%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	16 5.1%
Not Hispanic or Latino	300 94.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 0.9%
Asian	4 1.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	8 2.5%
White	297 94%
More than one race	3 0.9%
Unknown or Not Reported	1 0.3%
Region of Enrollment (participants) [Number]
United States	308 97.5%
Germany	8 2.5%
Body mass index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.3 (7.4)
Baseline current pain intensity 11-point NRS (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.59 (1.58)
Baseline Pain Interference score of the Brief Pain Inventory (BPI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.3 (1.75)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE)
Description	The primary endpoint of this trial was a binary endpoint assessing whether or not a participant experienced any TEAE.
Time Frame	Day 1 to Week 52

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
Measure Participants	316
Participants with TEAE	277 87.7%
Participants with serious TEAE	27 8.5%
Participants with non-serious TEAE	275 87%
Participants with unexpected TEAE	267 84.5%
Participants with related TEAE	190 60.1%
Participants with related serious TEAE	3 0.9%
Participants with TEAE leading to IMP discont.	12 3.8%
Participants with TEAE leading to trial discont.	6 1.9%

2. Secondary Outcome

Title	Number of Participants With Occurrence of Permanent Discontinuation From Treatment Due to an Adverse Event
Description	The investigator could choose to permanently discontinue a participant from treatment if continued exposure of the participant to neridronic acid could have posed an undue risk to the participant.
Time Frame	Day 1 to Day 10

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
Measure Participants	316
Count of Participants [Participants]	12 3.8%

3. Secondary Outcome

Title	Change From Baseline in the Current Pain Intensity Score
Description	The current Complex Regional Pain Syndrome (CRPS)-related pain intensity score was captured at each visit using an 11-point numerical rating scale where 0 = "no pain" and 10 = "pain as bad as you can imagine", a higher score indicates more pain.
Time Frame	Baseline to Week 12 and Week 26

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
Measure Participants	316
Baseline to Week 12	-1.54 (2.27)
Baseline to Week 26	-1.57 (2.45)

4. Secondary Outcome

Title	Number of Participants With Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score
Description	Participants with at least a 30 percent decrease in the current pain intensity score were considered to have responded to treatment.
Time Frame	Baseline, at Week 12 and Week 26

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
Measure Participants	316
At least 30% pain reduction - Week 12	105 33.2%
At least 30% pain reduction - Week 26	110 34.8%

5. Secondary Outcome

Title	Number of Participants With Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score
Description	Participants with at least a 50 percent decrease in the current pain intensity score were considered to have responded to treatment.
Time Frame	Baseline, at Week 12 and Week 26

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
Measure Participants	316
At least 50% pain reduction - Week 12	75 23.7%
At least 50% pain reduction - Week 26	74 23.4%

6. Secondary Outcome

Title	Patient Global Impression of Change (PGIC) at Week 12
Description	The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from "very much improved" to "very much worse". A response of "very much improved" or "much improved" is generally regarded as a clinically important improvement.
Time Frame	at Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set; 286 out of 316 participants attended the visit at Week 12 and were asked to complete the PGIC questionnaire.

Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
Measure Participants	286
Very Much Improved	31 9.8%
Much Improved	71 22.5%
Minimally Improved	98 31%
No Change	45 14.2%
Minimally Worse	23 7.3%
Much Worse	12 3.8%
Very Much Worse	3 0.9%
Missing	3 0.9%

7. Secondary Outcome

Title	Patient Global Impression of Change (PGIC) at Week 26
Description	The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from "very much improved" to "very much worse". A response of "very much improved" or "much improved" is generally regarded as a clinically important improvement.
Time Frame	at Week 26

Outcome Measure Data

Analysis Population Description

Full Analysis Set; 273 out of 316 participants attended the visit at Week 26 and were asked to complete the PGIC questionnaire.

Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
Measure Participants	273
Very Much Improved	38 12%
Much Improved	58 18.4%
Minimally Improved	84 26.6%
No Change	52 16.5%
Minimally Worse	25 7.9%
Much Worse	10 3.2%
Very Much Worse	2 0.6%
Missing	4 1.3%

8. Secondary Outcome

Title	Change in the Pain Interference Score of the Brief Pain Inventory (BPI)
Description	The Brief Pain Inventory (BPI) Interference Score is the mean value of 7 self-reported items in question 9 of the BPI Short Form Questionnaire. Participants rated their interference of pain with general activity, walking, work, sleep and other activities in the past 24 hours, with possible ratings from 0 (does not interfere) to 10 (completely interferes). The BPI interference Score ranges from 0 to 10, with higher values indicating greater pain interference of daily activities.
Time Frame	Baseline to Week 12 and Week 26

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
Measure Participants	316
Baseline to Week 12	-2.2 (2.49)
Baseline to Week 26	-2.1 (2.64)

Adverse Events

Time Frame	Day 1 to Week 52
Adverse Event Reporting Description	318 participants were allocated to treatment. Two participants did not meet inclusion criteria/met exclusion criteria, thus 316 participants were treated (Safety Set). Participants were questioned about possible adverse events with non-leading questions before administration of the IMP and at regular intervals thereafter. All adverse events reported spontaneously by participants at any time point were also documented. Treatment emergent adverse events are reported.
Arm/Group Title	Neridronic Acid
Arm/Group Description	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. Neridronic acid: Neridronic acid administered as intravenous infusion.
All Cause Mortality
	Neridronic Acid
	Affected / at Risk (%)	# Events
Total	1/316 (0.3%)
Serious Adverse Events
	Neridronic Acid
	Affected / at Risk (%)	# Events
Total	27/316 (8.5%)
Cardiac disorders
Angina unstable	1/316 (0.3%)	1
Myocardial infarction	1/316 (0.3%)	1
Stress cardiomyopathy	1/316 (0.3%)	1
Gastrointestinal disorders
Abdominal pain	1/316 (0.3%)	1
Colitis	1/316 (0.3%)	1
General disorders
Chest pain	2/316 (0.6%)	3
Condition aggravated	1/316 (0.3%)	1
Hepatobiliary disorders
Cholecystitis acute	1/316 (0.3%)	1
Liver disorder	1/316 (0.3%)	1
Infections and infestations
Pneumonia	2/316 (0.6%)	2
Injury, poisoning and procedural complications
Fall	2/316 (0.6%)	2
Procedural pain	1/316 (0.3%)	1
Musculoskeletal and connective tissue disorders
Myalgia	1/316 (0.3%)	1
Osteoarthritis	2/316 (0.6%)	2
Rotator cuff syndrome	1/316 (0.3%)	1
Nervous system disorders
Loss of consciousness	1/316 (0.3%)	1
Syncope	2/316 (0.6%)	2
Transient ischaemic attack	1/316 (0.3%)	1
Psychiatric disorders
Delirium	1/316 (0.3%)	1
Suicidal ideation	1/316 (0.3%)	1
Suicide attempt	2/316 (0.6%)	2
Reproductive system and breast disorders
Cystocele	1/316 (0.3%)	1
Surgical and medical procedures
Leg amputation	1/316 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Neridronic Acid
	Affected / at Risk (%)	# Events
Total	275/316 (87%)
Gastrointestinal disorders
Nausea	34/316 (10.8%)	46
General disorders
Fatigue	32/316 (10.1%)	39
Condition aggravated	30/316 (9.5%)	44
Pain	28/316 (8.9%)	37
Pyrexia	18/316 (5.7%)	19
Musculoskeletal and connective tissue disorders
Myalgia	52/316 (16.5%)	70
Arthralgia	27/316 (8.5%)	31
Back pain	25/316 (7.9%)	30
Pain in extremity	25/316 (7.9%)	30
Bone pain	17/316 (5.4%)	20
Nervous system disorders
Headache	65/316 (20.6%)	96

Limitations/Caveats

Due to the open-label, uncontrolled nature of the trial and the concomitant use of pain medication, the effect of neridronic acid on pain intensity and the side effect profile of neridronic acid have to be interpreted with care.

More Information

Certain Agreements

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

The sponsor reserves the right to review any proposed presentation of the results of this trial before they are submitted for publication or public disclosure. Neither party (e.g., the sponsor, the coordinating investigator) has the right to prohibit publication or public disclosure unless it can be shown to affect possible patent rights.