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

• ClinicalTrials.gov Identifier: NCT01323374
• Recruitment Status: Completed
• First Posted: March 25, 2011
• Last Update Posted: July 19, 2012
• Sponsor: Chelsea Therapeutics
• Information provided by (Responsible Party): Chelsea Therapeutics

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Fibromyalgia	Drug: Droxidopa; Drug: Carbidopa; Drug: Droxidopa/carbidopa; Drug: Placebo	Phase 2

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Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: January 2009
• Actual Primary Completion Date: October 2011
• Actual Study Completion Date: October 2011

Arms and Interventions

Arm	Intervention/treatment
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 Name: 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 Name: 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
Placebo Comparator: Placebo TID	Drug: Placebo; Oral, placebo TID; Other Name: Inactive ingrediant

Outcome Measures

Primary Outcome Measures :

1. Determine the efficacy of droxidopa and droxidopa/carbidopa in the treatment of pain associated with fibromyalgia [ Time Frame: Baseline to end of 8 week treatment period ]

Secondary Outcome Measures :

1. Evaluate the effect of droxidopa and combinations of droxidopa/carbidopa on signs and symptoms of fibromyalgia (including depression, fatigue, and sleep disorder) [ Time Frame: Baseline to end of 8 week treatment period ]
2. Evaluate the effect of droxidopa and combinations of droxidopa/carbidopa on the overall quality of life of fibromyalgia patients [ Time Frame: Baseline to end of 8 week treatment period ]
3. 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 [ Time Frame: Baseline to end of 8 week treatment period ]
4. 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 [ Time Frame: Baseline to end of 8 week treatment period ]
5. Estimate the optimal dose for relief of fibromyalgia pain using response surface methodology [ Time Frame: Baseline to end of 8 week treatment period ]
6. 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. [ Time Frame: Baseline to end of 4 week follow-up period following 8 week treatment period ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United Kingdom

Rheumatology Department; Barnsley Hospital NHS Foundation Trust

Barnsley, United Kingdom, S75 2EP

MAC UK Neuroscience

Liverpool, United Kingdom, L18 1HQ

Academic Dept of Rheumatology, Kings College London

London, United Kingdom, SE5 9RJ

MAC UK Neuroscience

Manchester, United Kingdom, M32 0UT

Musculoskeletal Department; Freeman Hospital

Newcastle Upon Tyne, United Kingdom, NE7 7DN

Rheumatology Department, Poole Hospital NHS Trust

Poole, United Kingdom, BH15 2JB

Clinical Trials Unit; Main Hospital; Salford Rooyal NHS Foundation Trust

Salford, United Kingdom, M6 8HD

Sponsors and Collaborators

Chelsea Therapeutics

Investigators

• Principal Investigator: Ernest Choy, M.D.; Academic Dept of Rheumatology Kings College London

More Information

• Responsible Party: Chelsea Therapeutics
• ClinicalTrials.gov Identifier: NCT01323374 History of Changes
• Other Study ID Numbers: Droxidopa FMS201
• First Posted: March 25, 2011
• Last Update Posted: July 19, 2012
• Last Verified: July 2012

Keywords provided by Chelsea Therapeutics:

Fibromyalgia; FMS; droxidopa; pain

Additional relevant MeSH terms:

Fibromyalgia; Myofascial Pain Syndromes; Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases; Carbidopa; Droxidopa; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Aromatic Amino Acid Decarboxylase Inhibitors; Enzyme Inhibitors