Study To Assess The Clinical Benefit Of Droxidopa And Droxidopa/Carbidopa In Subjects With Fibromyalgia (FMS201)

A Phase II, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Response, Study To Assess The Clinical Benefit Of Droxidopa and Droxidopa/Carbidopa In Subjects With Fibromyalgia

A correlation between increased norepinephrine concentration in the central nervous system (CNS) and a decrease in fibromyalgia pain has been suggested in clinical studies. Therefore, as a pro-drug of norepinephrine, droxidopa could potentially benefit fibromyalgia patients by reducing pain as a result of increasing CNS levels of norepinephrine.

As this benefit is presumed to be a central effect, the addition of carbidopa, a peripheral DOPA decarboxylase (DDC) inhibitor, may favorably impact the drug's treatment profile. Carbidopa is utilized as a blocker of peripheral DDC, an enzyme required for the conversion of droxidopa into norepinephrine. Therefore, inhibition of peripheral DDC should result in a reduction of any side effects resulting from the peripheral production of norepinephrine, whilst allowing for increased central levels, and hence, increased centrally mediated benefits.

The purpose of the study is the obtain information regarding the proper dosing, effectiveness and safety of droxidopa and combination droxidopa/carbidopa treatments in patients with fibromyalgia.

Study Overview

• Status: Completed
• Conditions: Fibromyalgia
• Intervention / Treatment: Drug: Droxidopa; Drug: Carbidopa; Drug: Droxidopa/carbidopa; Drug: Placebo

Detailed Description

Fibromyalgia syndrome (FMS) and Chronic widespread pain (CWP) are two syndromes within a broader class known as functional somatic syndromes. Chronic widespread pain (CWP) is defined according to the American College of Rheumatology (ACR), as pain both above and below the waist involving both sides of the body and lasting for at least 3 months. Fibromyalgia syndrome (FMS), a subset of CWP, is a multisystem disease characterized by sleep disturbance, fatigue, headache, morning stiffness, paresthesias, and anxiety.

While there is debate as to specific etiology and pathogenesis, fibromyalgia is generally believed to be the result of a perturbation of central pain processing, specifically the neuroendocrine system. Fibromyalgia patients have been shown to have lower levels of metabolites from three neurotransmitters (serotonin, norepinephrine, and dopamine) in their cerebrospinal fluid (CSF) compared to healthy controls. The low rate of turnover of these neurotransmitters supports the hypothesis of a metabolic defect in fibromyalgia and suggests that the defect occurs at a neuroregulatory level. Results of a study that examined the effect of a permanent reduction in the noradrenergic innervation of the spinal cord suggested that the antinociceptive effects of norepinephrine are closely linked to opioidergic and tachykinergic neurotransmission.

Droxidopa [also, known as L-threo-3,4-dihydroxyphenylserine, L-threo-DOPS, or L-DOPS] is the International non-proprietary name (INN) for a synthetic amino acid precursor of norepinephrine (NE), which was originally developed by Sumitomo Pharmaceuticals Co., Limited, Japan. It has been approved for use in Japan since 1989. Droxidopa has been shown to improve symptoms of orthostatic hypotension that result from a variety of conditions including Shy Drager syndrome (Multiple System Atrophy), Pure Autonomic Failure, and Parkinson's disease. There are four stereoisomers of DOPS; however, only the L-threo-enantiomer (droxidopa) is biologically active. Data from clinical studies and post-marketing surveillance programs conducted in Japan show that the most commonly reported adverse drug reactions with droxidopa are increased blood pressure, nausea, and headache. In clinical studies to date, data suggests that droxidopa is well-tolerated and effective as a norepinephrine precursor.

Pre-clinical and clinical studies suggest that droxidopa has an analgesic effect in patients with chronic pain. An increase in central nervous system (CNS) levels of norepinephrine has been shown to correlate with an analgesic effect. Based on the pre-clinical and clinical findings to date, it is hypothesized that droxidopa can provide pain reduction in fibromyalgia patients through increasing the CNS levels of norepinephrine.

Carbidopa is a DOPA decarboxylase (DDC) inhibitor. At therapeutic doses carbidopa does not cross the blood-brain barrier and therefore should not inhibit CNS metabolism of droxidopa to NE. Decreasing the activity of DDC in the periphery enables droxidopa metabolism to be focused in the CNS. This CNS focus should increase CNS response while also limiting the increase in blood pressure associated with peripheral droxidopa metabolism. In addition, as DDC is an enzyme required for the conversion of droxidopa into its active metabolite norepinephrine, inhibition of peripheral DDC, utilizing Carbidopa, should result in a reduction of any side effects resulting from the peripheral production of NE, whilst allowing for increased central levels, and hence, increased centrally mediated benefits.

The primary objective of this study is to determine the efficacy of droxidopa and droxidopa/carbidopa in the treatment of pain associated with fibromyalgia. Secondary objectives include: evaluation of the effect of droxidopa and combinations of droxidopa/carbidopa on signs and symptoms of fibromyalgia, evaluation of the effect of droxidopa and combinations of droxidopa/carbidopa on the overall quality of life of fibromyalgia patients, evaluation of the dose-response relationship for droxidopa between different doses of droxidopa, carbidopa and combinations of droxidopa/carbidopa in fibromyalgia patients, evaluation of the clinical benefit of treatment with different doses of droxidopa, carbidopa and combinations of droxidopa/carbidopa in fibromyalgia patients, estimation of the optimal dose for relief of fibromyalgia pain using response surface methodology, and evaluation of the safety of droxidopa and droxidopa/carbidopa treatments.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Barnsley, United Kingdom, S75 2EP
    • Rheumatology Department; Barnsley Hospital NHS Foundation Trust
  • Liverpool, United Kingdom, L18 1HQ
    • MAC UK Neuroscience
  • London, United Kingdom, SE5 9RJ
    • Academic Dept of Rheumatology, Kings College London
  • Manchester, United Kingdom, M32 0UT
    • MAC UK Neuroscience
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Musculoskeletal Department; Freeman Hospital
  • Poole, United Kingdom, BH15 2JB
    • Rheumatology Department, Poole Hospital NHS Trust
  • Salford, United Kingdom, M6 8HD
    • Clinical Trials Unit; Main Hospital; Salford Rooyal NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female and aged 18 years or over
• Clinical diagnosis of fibromyalgia as defined by the 1990 American College of Rheumatology (ACR) criteria
• Provide written informed consent to participate in the study and understand that they may withdraw their consent at any time without prejudice to their future medical care
• Have a score of between 20mm and 90mm on the Visual Analog Scale for Pain (VAS-P) section of the SF-MPQ at screening and baseline visits

Exclusion Criteria:

• Have uncontrolled hypertension (defined as systolic blood pressure >160 mmHg and/or diastolic blood pressure >110 mmHg) or use of ≥2 antihypertensive medications
• Patients currently taking pregabalin; unless they provide written informed consent and agree to discontinue pregabalin use 3 weeks prior to other screening procedures and for the duration of the study
• Currently taking tri-cyclic antidepressant medication
• Currently taking any norepinephrine re-uptake inhibitors
• Have clinically relevant depression noted as significant by a score greater than 17 on the Hamilton Depression Scale (HAM-D)
• History of known or suspected drug or substance abuse
• Women of childbearing potential who are not using a medically accepted contraception (Reproductive potential: Female subjects should be either post-menopausal (amenorrhea for at least 12 consecutive months), surgically sterile, or women of child-bearing potential (WOCP) who are using or agree to use acceptable methods of contraception throughout the study period and for 4 weeks after the last dose of investigational product. Acceptable contraceptives include intrauterine devices (IUDs), hormonal contraceptives (oral, depot, patch or injectable) and double barrier methods such as condoms or diaphragms with spermicidal gel or foam. If hormonal contraceptives are used they should be taken according to the package insert. WOCP who are not currently sexually active must agree to use acceptable contraception, as defined above, if they decide to become sexually active during the period of the study and for 4 weeks after the last dose of investigational product. For WOCP a urine pregnancy test must be conducted at screening, baseline and study termination; the results must be negative at screening and at baseline. Any positive result will be confirmed by serum beta HCG pregnancy test).
• Sexually active males whose partner is a WOCP must agree to use condoms for the duration of the study and for 4 weeks after the last dose
• Women who are pregnant, breast feeding, or plan to become pregnant during the course of this study
• Known or suspected hypersensitivity to the study medication or any of its ingredients
• Have in the investigator's opinion any significant cardiac arrhythmia
• Any significant systemic, hepatic, cardiac or renal illness
• Diabetes mellitus or insipidus
• Have a history of closed angle glaucoma
• Have a known or suspected current malignancy. Patients with a history of cancer must be symptom- and treatment-free for at least 5 years prior to randomization, with the exception of patients with non-melanoma, non-invasive skin cancers (such as basal cell carcinoma), who should not have had an intervention or recurrence within one year of starting the study
• Patients with known gastrointestinal illness or other gastrointestinal disorder that may, in the investigator's opinion, affect the absorption of study drug
• In the investigator's opinion, have clinically significant abnormalities on clinical examination or laboratory testing
• In the investigator's opinion, are unable to adequately co-operate because of individual or family situation
• In the investigator's opinion, are suffering from a mental disorder that interferes with the diagnosis and/or with the conduct of the study, e.g. schizophrenia, major depression, dementia
• Are not able or willing to comply with the study requirements for the duration of the study
• Have participated in another clinical trial with an investigational agent (including named patient or compassionate use protocol) within 1 month before the start of the study
• Previous enrollment in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo TID	Drug: Placebo; Oral, placebo TID; Other Names: Inactive ingrediant
Experimental: Droxidopa 200mg TID	Drug: Droxidopa; Oral, 200mg, 400mg or 600mg TID, duration includes up to a 1 week blinded titration period followed by an 8 week treatment period.; Other Names: L-threo-3,4-dihydroxyphenylserine; L-threo-DOPS; L-DOPS
Experimental: Droxidopa 400mg TID	Drug: Droxidopa; Oral, 200mg, 400mg or 600mg TID, duration includes up to a 1 week blinded titration period followed by an 8 week treatment period.; Other Names: L-threo-3,4-dihydroxyphenylserine; L-threo-DOPS; L-DOPS
Experimental: Droxidopa 600mg TID	Drug: Droxidopa; Oral, 200mg, 400mg or 600mg TID, duration includes up to a 1 week blinded titration period followed by an 8 week treatment period.; Other Names: L-threo-3,4-dihydroxyphenylserine; L-threo-DOPS; L-DOPS
Active Comparator: Carbidopa 25mg TID	Drug: Carbidopa; Oral, 25mg, or 50mg TID, duration includes up to a 1 week blinded titration period followed by an 8 week treatment period.; Other Names: Lodosyn
Active Comparator: Carbidopa 50 mg TID	Drug: Carbidopa; Oral, 25mg, or 50mg TID, duration includes up to a 1 week blinded titration period followed by an 8 week treatment period.; Other Names: Lodosyn
Experimental: Droxidopa/carbidopa 200mg/25mg TID	Drug: Droxidopa/carbidopa; Oral, 200mg/25mg, 400mg/25mg, 600mg/25mg, 200mg/50mg, 400mg/50mg, or 600mg/50mg TID. Duration includes up to a 1 week titration period followed by an 8 week treatment period.; Other Names: L-threo-3,4-dihydroxyphenylserine / Lodosyn; L-threo-DOPS / Lodosyn; L-DOPS / Lodosyn
Experimental: Droxidopa/carbidopa 400mg/25mg TID	Drug: Droxidopa/carbidopa; Oral, 200mg/25mg, 400mg/25mg, 600mg/25mg, 200mg/50mg, 400mg/50mg, or 600mg/50mg TID. Duration includes up to a 1 week titration period followed by an 8 week treatment period.; Other Names: L-threo-3,4-dihydroxyphenylserine / Lodosyn; L-threo-DOPS / Lodosyn; L-DOPS / Lodosyn
Experimental: Droxidopa/carbidopa 600mg/25mg TID	Drug: Droxidopa/carbidopa; Oral, 200mg/25mg, 400mg/25mg, 600mg/25mg, 200mg/50mg, 400mg/50mg, or 600mg/50mg TID. Duration includes up to a 1 week titration period followed by an 8 week treatment period.; Other Names: L-threo-3,4-dihydroxyphenylserine / Lodosyn; L-threo-DOPS / Lodosyn; L-DOPS / Lodosyn
Experimental: Droxidopa/carbidopa 200mg/50mg TID	Drug: Droxidopa/carbidopa; Oral, 200mg/25mg, 400mg/25mg, 600mg/25mg, 200mg/50mg, 400mg/50mg, or 600mg/50mg TID. Duration includes up to a 1 week titration period followed by an 8 week treatment period.; Other Names: L-threo-3,4-dihydroxyphenylserine / Lodosyn; L-threo-DOPS / Lodosyn; L-DOPS / Lodosyn
Experimental: Droxidopa/carbidopa 400mg/50mg TID	Drug: Droxidopa/carbidopa; Oral, 200mg/25mg, 400mg/25mg, 600mg/25mg, 200mg/50mg, 400mg/50mg, or 600mg/50mg TID. Duration includes up to a 1 week titration period followed by an 8 week treatment period.; Other Names: L-threo-3,4-dihydroxyphenylserine / Lodosyn; L-threo-DOPS / Lodosyn; L-DOPS / Lodosyn
Experimental: Droxidopa/carbidopa 600mg/50mg TID	Drug: Droxidopa/carbidopa; Oral, 200mg/25mg, 400mg/25mg, 600mg/25mg, 200mg/50mg, 400mg/50mg, or 600mg/50mg TID. Duration includes up to a 1 week titration period followed by an 8 week treatment period.; Other Names: L-threo-3,4-dihydroxyphenylserine / Lodosyn; L-threo-DOPS / Lodosyn; L-DOPS / Lodosyn

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Determine the efficacy of droxidopa and droxidopa/carbidopa in the treatment of pain associated with fibromyalgia	Baseline to end of 8 week treatment period

Secondary Outcome Measures

Outcome Measure	Time Frame
Evaluate the effect of droxidopa and combinations of droxidopa/carbidopa on signs and symptoms of fibromyalgia (including depression, fatigue, and sleep disorder)	Baseline to end of 8 week treatment period
Evaluate the effect of droxidopa and combinations of droxidopa/carbidopa on the overall quality of life of fibromyalgia patients	Baseline to end of 8 week treatment period
Evaluate the dose-response relationship for droxidopa (200, 400, and 600mg TID), carbidopa (25 and 50mg TID) and combinations of droxidopa/carbidopa (200/25, 200/50, 400/25, 400/50, 600/25 and 600/50mg TID) in the treatment of fibromyalgia patients	Baseline to end of 8 week treatment period
Evaluate the clinical benefit of treatment with 200, 400, and 600mg droxidopa TID, or 25 and 50mg carbidopa TID and combinations of droxidopa/carbidopa 200/25, 200/50, 400/25, 400/50, 600/25 and 600/50mg TID in the treatment of fibromyalgia patients	Baseline to end of 8 week treatment period
Estimate the optimal dose for relief of fibromyalgia pain using response surface methodology	Baseline to end of 8 week treatment period
Evaluate the safety of droxidopa and droxidopa/carbidopa treatments based on the occurrence of treatment-emergent adverse events (AE) and specific evaluation of blood pressure, heart rate, ECG, and laboratory findings across the study.	Baseline to end of 4 week follow-up period following 8 week treatment period

Collaborators and Investigators

• Sponsor: Chelsea Therapeutics
• Investigators: Principal Investigator: Ernest Choy, M.D., Academic Dept of Rheumatology Kings College London

Publications and helpful links

Helpful Links

• EudraCT summary results

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: March 24, 2011
• First Submitted That Met QC Criteria: March 24, 2011
• First Posted (Estimated): March 25, 2011

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: pain; droxidopa; Fibromyalgia; FMS
• Additional Relevant MeSH Terms: Nervous System Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Muscular Diseases; Neuromuscular Diseases; Fibromyalgia; Myofascial Pain Syndromes; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Droxidopa; Carbidopa
• Other Study ID Numbers: Droxidopa FMS201