343 posters, 5 videos, 2 audios, 18 topics, 33 sessions, 263 authors, 202 institutions

24th Annual Pain Medicine Meeting 2025

November 13-15, 2025| JW Marriott Austin, Austin, Texas

2184566

Pivotal phase 3 trial of neridronate in Complex Regional Pain Syndrome Type 1: CRPS-RISE study design and methodology

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Poster Presenter

Amarita Randhawa

Authors

Amarita Randhawa

Affiliations

Ambros Therapeutics, Inc

Part of Topic

Scientific Abstracts > Chronic Pain

TITLE:

Pivotal Phase 3 Trial of Neridronate in Complex Regional Pain Syndrome Type-1: CRPS-RISE Study Design and Methodology

AUTHORS:

Srinivasa N. Raja, MD, Michael Rowbotham, MD, Gail Cawkwell, MD, PhD, Amarita S. Randhawa, PharmD, Monica Salamea, Stephen Bruehl, PhD

BACKGROUND:

• Complex Regional Pain Syndrome Type-1 (CRPS-1) is a rare, chronic, and often disabling condition. There are no FDA-approved medicines, and few therapies demonstrate efficacy in rigorous clinical trials.[1]
• Neridronate, approved for treatment of CRPS in Italy,[2-4] is an alkyl-aminobisphosphonate believed to impact CRPS-1 via multiple mechanisms, including bone-targeting and immunomodulatory actions as well as anti-inflammatory effects.[5-7]
• In the Italian phase 3 registrational trial, a significant improvement in pain intensity was observed within the first 20 days of treatment with intravenous (IV) neridronate 400 mg vs placebo (p=0.043).[3]
• The intended population for the planned Phase 3 trial of neridronate for CRPS-1, CRPS-RISE, leverages a precision medicine approach believed to improve the odds of identifying patients with CRPS-1 most likely to respond to neridronate based on its proposed mechanisms of action and analysis of prior trials. Specifically, patients with the warm CRPS-1 subtype (edema, red/warm skin) and a positive triple phase bone scan may be most likely to respond.

OBJECTIVE:

• To present the study design and methods of CRPS-RISE, which aims to evaluate the efficacy, safety, and tolerability of IV neridronate for the treatment of CRPS-1.

METHODS

Design & Eligibility:

• CRPS-RISE (NCT07210515) is a phase 3, multicenter, randomized, triple-blind, placebo-controlled trial evaluating the efficacy, safety, and tolerability of IV neridronate for the treatment of CRPS-1.

• ~270 participants who satisfy all eligibility criteria (key criteria in Table 1) will be enrolled in the trial across ~60 sites in the US.

• The trial includes a screening, treatment, and follow-up period (Figure 1).

• Eligible participants will be randomized to receive either neridronate or matching placebo in a 1:1 ratio.

Concomitant Treatments and Therapies
• All participants will take supplemental calcium and vitamin D (standard of care for participants treated with bisphosphonates).
• Stable doses of many medicines and therapies are allowed to continue during the trial. For example:
• Analgesics, such as acetaminophen, nonsteroidal anti-inflammatory drugs, opioids ≤ 45 morphine equivalents/day, and neuropathic therapies (e.g., gabapentinoids)
• Physical therapy, occupational therapy, rehabilitation modalities, psychological or psychiatric modalities

Rescue Treatment

• Rescue medications are permitted to treat pain and include:

• 1st line: Acetaminophen, with a total daily dose ≤ 4 grams/day

• 2nd line: For moderate to severe pain (e.g., > 4 on 0-10 scale) that persist 30 min after acetaminophen was taken as rescue, oxycodone 5 mg immediate release may be taken (up to 4 times/day)

Prophylaxis of Acute Phase Reaction
• Short-term use of IV bisphosphonates, as in the case of this trial, is generally well-tolerated, with the most common adverse event expected to be acute phase reaction.

• Acute phase reaction typically presents with the first infusion as ‘flu like’ illness; mostly self-limiting with resolution within 24 to 72 hours.

• Participants will be prophylactically treated with oral acetaminophen 1 hour prior to the first infusion.

Endpoints & Assessments:

• The trial is well-powered for the primary endpoint (> 90%) and key secondary efficacy endpoints (> 80%).

• The primary objective is to assess the efficacy of neridronate vs placebo based on change from baseline to Week 12 in pain intensity per 7-day diary averages (11-point NRS) (Figure 2).

• Key secondary endpoints (analyzed in a hierarchical manner) include:

• ≥ 50% pain reduction from baseline to Week 12 in pain intensity using the 7-day dairy averages on the 11-point NRS

• Change from baseline to Week 12 in CRPS Severity Score (CSS)

• Patient Global Impression of Change in CRPS-related health at Week 12

• Change from baseline to Week 12 in the Short Form Health Survey (SF-36), Physical Functioning domain

• Other secondary endpoints include assessments of percent reduction in average pain intensity from baseline to various time points (e.g., ≥ 30% reduction at Day 10), sleep disturbance, time to onset of analgesia, range of motion, pain with active motion, SF-36, McGill Pain Questionnaire, use of rescue medications, and warm CRPS clinical features.

• Safety and tolerability will be evaluated by incidence, seriousness, and severity of treatment-emergent adverse events; treatment emergent adverse events leading to discontinuation; values and changes from baseline in physical exams, vital signs, labs, and cardiac monitoring.

Site Selection & Enrollment Considerations:
• Site selection across the US is ongoing, and enrollment is expected to begin in the first quarter of 2026.
• For participants who are not close to an investigative site, transportation and accommodation will be offered.
• Participants may have low vitamin D levels at screening, which is common in the U.S. There will be an opportunity to supplement and increase vitamin D levels during screening, as needed.

DISCUSSION

• Neridronate's efficacy and safety in patients with early CRPS are supported by over 10 years of research and real-world clinical use in Italy.
• Pain specialists are uniquely positioned to identify CRPS-1 patients, who may be eligible to enroll in this pivotal clinical trial evaluating the efficacy and safety of neridronate, which has the potential to be the first FDA-approved medicine for CRPS-1.

KEY TAKEAWAYS

• CRPS-RISE is a pivotal trial evaluating the bisphosphonate, neridronate, as an investigational treatment for CRPS-1, a rare disease that carries substantial burden for CRPS-1 patients, healthcare professionals, and the healthcare system.
• A key element of this trial's design is the precision medicine approach, an approach intended to improve the odds of identifying participants who are most likely to respond to neridronate: those with early, warm CRPS-1 and a positive triple phase bone scan.
• Given the progressive nature of CRPS and the different subtypes, it is important to consider a precision medicine approach that targets the right treatments to the right patients at the right time.
• There is a critical need for innovation and research to find safe and effective treatments that not only manage CRPS symptoms but also help prevent disease progression.

REFERENCES

1. Harden RN, et al. Pain Med. 2022;23(Suppl 1):S1-S53.
2. NERIXIA SmPC. Abiogen Pharma S.p.A. August 2024.
3. Varenna M, et al. Rheumatology. 2013;52(3):534-542.
4. Varenna M, et al. Ther Adv Musc Dis. 2021;13:1759720X211014020.
5. Wang L, et al. Anesth Analg. 2016; 123(4):1033-1045.
6. Varenna M, et al. Calcif Tissue Int. 2024;115(3):251-259.
7. Varenna M, et al. Osteoporos Int. 2025;36(4):737-740.