Evaluation of IV AMBTX-01 (Neridronate) for Treatment of CRPS Type 1 (CRPS-RISE)

A Randomized, Triple-blind, Placebo-controlled, Phase 3 Trial to Evaluate the Efficacy, Safety, and Tolerability of Intravenous AMBTX-01 (Neridronate) for Treatment of Complex Regional Pain Syndrome Type 1 (CRPS-RISE)

Phase 3 Trial of AMBTX-01 (neridronate) for Complex Regional Pain Syndrome Type 1

This is a multicenter, randomized, triple-blind, controlled trial, to assess the efficacy, safety, and tolerability of neridronate 400 mg IV in adult participants with the warm subtype of Complex Regional Pain Syndrome Type 1 (CRPS-1) and a positive triple phase bone scan (TPBS).

The total planned trial duration for each participant will be approximately up to 18 weeks and will include:

• Screening period of 2 up to 6 weeks
• Treatment period on Days 1, 4, 7, and 10
• Post-treatment follow-up through week 12

Inclusion Criteria:

1. Male or female participant ≥ 18 years of age at time of Screening.

2. A diagnosis of CRPS-1 according to the clinical Budapest Criteria as recommended by the International Association for the Study of Pain (IASP), as well as no known peripheral nerve injury. Signs and symptoms of CRPS must apply to a single identified affected limb (i.e., arm, hand, wrist, leg, ankle or foot) and must demonstrate asymmetry with respect to the contralateral limb.

3. Single affected limb at the Screening and Randomization Visits meeting the following warm subtype criteria:

   1. Edema in the affected limb

   2. AND ≥ 2 of the following:

      1. Obvious redness in the affected region relative to the same region on the contralateral limb on inspection
      2. ≥ 1°C increase in temperature on the affected limb relative to the contralateral limb
      3. Moderate-to-severe edema

4. ≤ 6 months since the onset of CRPS symptoms relative to the Randomization visit

5. Increased uptake in the involved limb compared to the contralateral limb on TPBS (phase 2 and/or phase 3) during Screening. A historic scan not older than 3 months prior to Randomization Visit is acceptable, if available and of sufficient quality for a central read.

6. Women of childbearing potential must:

   1. Be nonpregnant.
   2. Be nonlactating.
   3. Agree to use a highly effective method of contraception and for at least 6 months following last investigational product administration.

   Exception: Women exclusively engaging in same sex sexual activities are not required to meet this criterion.

7. Adequate compliance with the eDiary during the screening period.

Exclusion Criteria

1. A current or prior diagnosis of CRPS Type 2 or CRPS not otherwise specified (CRPS NOS), or whose CRPS has no known inciting event, or CRPS-1 without criteria of the warm subtype at the time of Screening.

2. ≥ 40 points on the Pain Catastrophizing Scale.

3. Prior use of neridronate or participation in a clinical study where the participant may have received neridronate.

4. The use of any of the following treatments within the timeframe specified from Randomization Visit:

   1. Within the last 12 months:

      • IV bisphosphonates
      • IV immunoglobulin

   2. Within the last 6 months:

      • Any oral bisphosphonate, denosumab (Prolia®) or receptor activator of nuclear factor kappa B ligand (RANKL) inhibitors (e.g., denosumab biosimilar compounds)
      • Calcitonin
      • Ketamine
      • Radiation therapy to the head or neck

5. Participants currently taking or planning to be treated with prohibited concomitant medications/therapies, or not likely able to follow the protocol restrictions for use of concomitant treatment.

6. Severely impaired renal function.

7. Hypocalcemia.

8. Vitamin D deficiency.

9. Significant dental findings such as an unhealed tooth extraction site.

10. Eye inflammation.

11. Significantly elevated liver-related lab tests or evidence of significant liver disease.

12. Clinically unstable cardiac disease.

13. Any known conditions, from 3 months prior to Screening Visit or to the Randomization Visit, that may interfere with the assessment of CRPS-1, CRPS-related pain, safety, or other trial assessments.