Placebo-Controlled Study to Investigate the Efficacy & Safety of Injectafer in the Treatment of RLS

A Double-Blinded, Multi-Center, Randomized, Placebo-Controlled Study to Investigate the Efficacy and Safety of Injectafer (Ferric Carboxymaltose) in the Treatment of Restless Legs Syndrome (RLS)

This will be a Phase III, double blinded, multi-center, randomized, placebo-controlled study. Eligible subjects will be randomized in a 1:1 ratio to receive Injectafer or Placebo on days 0 and 5. All treated subjects will be followed for efficacy and safety for 12 months. The subject's participation in the study will be for approximately 1 year from Day 0.

This will be a Phase III, double blinded, multi-center, randomized, placebo-controlled study. Eligible subjects will be randomized in a 1:1 ratio to receive Injectafer or Placebo on days 0 and 5. All treated subjects will be followed for efficacy and safety for 12 months. Subjects will visit the clinic on Days 0 and 5 for treatment, and then on Days 14, 42, 168, and 365. In between the clinic visits subjects will be contacted remotely on Days 84, 126, 210, 252, 294, and 336. The subject's participation in the study will be for approximately 1 year from Day 0.

Inclusion Criteria:

1. Male or female subject's ≥18 years of age, willing and able to give informed consent to the study.

2. RLS symptoms affirming diagnosis. The IRLS Diagnostic Criteria must be met:

   1. An urge (distressing need) to move the legs usually associated with painful or uncomfortable sensations in the legs. The urge to move may be present without the uncomfortable sensations. The arms or other body parts may be involved in addition to the legs.
   2. The urge to move or unpleasant sensations are worse or exclusively present at rest or inactivity, such as lying down or sitting.
   3. The urge to move or unpleasant sensations are partially/temporarily relieved with walking or moving the legs.
   4. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night. When symptoms are severe, the worsening at night may not be noticeable but must have been previously present.

3. Subjects should be on monotherapy for RLS. Treatment should be stable for at least 8 weeks prior to screening (See approved RLS Therapies/Regimen in Appendix III).

4. A score ≥15 on the IRLS Rating Scale at screening and on Day 0 prior to dosing.

5. Subjects on anti-depressants and sleep medications must be on a stable dose for at least 6 months.

6. Subject has regular sleep hours between 9 pm and 9 am.

7. Subjects at risk for pregnancy must have a negative pregnancy test at baseline and be practicing an acceptable form of birth control: have had a hysterectomy or tubal ligation, or otherwise be incapable of pregnancy, or have practiced any of the following methods of contraception for at least one month prior to study entry: hormonal contraceptives, spermicide with barrier, intrauterine device, or partner sterility.

Exclusion Criteria:

1. RLS 2° to other disease or injury.
2. Disorders that require treatment with the same medications used for RLS include: peripheral neuropathy and neurodegenerative disorders (i.e. Parkinson's Disease or Dementia).
3. Stage 4 - 5 CKD, subjects on dialysis or anticipated to start dialysis while participating in this study.
4. Any pain related (e.g., frequent muscle cramps, myalgia, fibromyalgia) or sleep related disorders (e.g. sleep apnea, unless on stable Continuous Positive Airway Pressure [CPAP]) which may confound the outcome measures.
5. Subjects with multiple sclerosis.
6. History of neuroleptic akathisia.
7. Parenteral iron use within 6 weeks prior to screening.
8. History of >10 blood transfusions in the past 2 years.
9. Anticipated need for blood transfusion during the study.
10. Known hypersensitivity reaction to any component of Injectafer® (Ferric Carboxymaltose).
11. Previously randomized to Injectafer® (FCM or VIT-45) in a clinical trial.
12. Current, active or acute or chronic infection other than viral upper respiratory tract infection
13. Malignancy (other than basal or squamous cell skin cancer or the subject has been cancer free for ≥ 5 years).
14. Pregnant or lactating women.
15. Seizure disorder currently being treated with medication.
16. Baseline ferritin ≥300 ng/mL.
17. Baseline TSAT ≥45%.
18. History of hemochromatosis, hemosiderosis, or other iron storage disorders.
19. AST or ALT greater than 2 times the upper limit of normal (ULN).
20. Hemoglobin greater than the ULN.
21. Known positive hepatitis B antigen (HBsAg), unless positive test can be attributed to receipt of hepatitis B vaccination in childhood or hepatitis C viral antibody (HCV) with evidence of active hepatitis (i.e., AST/ALT greater than the upper limit of normal).
22. Known positive HIV-1/HIV-2 antibodies (anti-HIV).
23. Received an investigational drug within 30 days before randomization.
24. Chronic alcohol or drug abuse within the past 6 months.
25. Any other pre-existing laboratory abnormality, medical condition or disease, which per the investigator may put the subject at risk if they participate in the study.
26. Subject unable or unwilling to comply with the study requirements.