Study of Droxidopa Treatment in Adults With Attention Deficit Hyperactivity Disorder With Co-administration of Carbidopa (ADD201)

A Two-Period Trial (Open-Label and Randomized Placebo-Controlled Substitution) of Droxidopa Treatment in Adults With ADHD With Co-administration of Carbidopa

Attention Deficit Hyperactivity Disorder (ADHD) is a neurobiological disorder characterized by lifelong issues of inattention, distraction, organizational difficulties, forgetfulness, restlessness, talking out of turn, difficulty waiting and interrupting others. ADHD is the second most common neuropsychiatric disorder affecting 4.4% of the United States (US) adult population, or between 8-9 million individuals.

Droxidopa (L-dihydroxyphenylserine (L-DOPS)) is a synthetic catecholamine which is converted to norepinephrine (NE) via decarboxylation, resulting in increased levels of NE centrally in the central nervous system (CNS) and peripherally. Co-treatment with carboxylase inhibitors, such as carbidopa, given with droxidopa, can increase the CNS levels of NE with greater crossing of the blood-brain barrier. Droxidopa has received orphan drug approval by the Food and Drug Administration (FDA) for the treatment of symptomatic neurogenic orthostatic hypotension in individuals with primary autonomic failure. The half-life of droxidopa is approximately 2-3 hours, resulting in administration three times daily.

Study Overview

• Status: Completed
• Conditions: Attention Deficit Hyperactivity Disorder
• Intervention / Treatment: Drug: Droxidopa+Carbidopa

Detailed Description

This will be a 12-week study of twenty enrolled participants with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria adult ADHD (age 18-55), with a goal of completing twenty participants in the trial. The primary objective of this study is to determine the effect of droxidopa therapy on adult ADHD symptoms over the course of a six-week open-label titration period followed by a two-week double-blind, placebo-controlled period. The primary outcome measure will be changes from baseline in total score on the Adult ADHD Investigator Symptom Rating Scale (AISRS). Secondary measures will be changes in self-reported ADHD symptoms on the Adult ADHD Self-Report Scale (ASRS v1.1) and global impairment on the Clinician Global Impression Scale (CGI).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10010
      • VA New York Harbor Healthcare System/New York University Langone Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. At the time of consent, are between the ages of 18-55, inclusive.
2. Meet DSM-IV criteria for ADHD as assessed by the Adult ADHD Clinician Diagnostic Scale (ACDS) v1.2.
3. Concomitant Axis I diagnoses that are allowed include social anxiety disorder or dysthymia which does not require treatment. Psychiatric co-morbidities will be diagnosed with the Structured Clinical Interview for DSM-IV Axis Disorders (SCID).
4. Must have a satisfactory medical assessment with no clinically significant abnormalities as determined by medical history, physical exam, electrocardiogram (ECG), and clinical laboratory testing.
5. Must be able to swallow capsules.
6. In the opinion of the investigator, the participant must understand and be able, willing and likely to fully comply with the study procedures and restrictions.
7. Must have given signed and dated informed consent in accordance with Good Clinical Practice (GCP) Guidelines.

Exclusion Criteria:

1. Lifetime or present history of bipolar or psychotic disorders, that in the investigator's opinion, interfere with the diagnosis and/or with the conduct of the study.
2. Uncontrolled comorbid major depressive disorder, anxiety disorder or dysthymia.
3. Women of childbearing potential who are not using a medically accepted contraception.
4. Sexually active males whose partner is a woman of child-bearing potential must agree to use condoms for the duration of the study and for 4 weeks after the last dose.
5. Women who are pregnant, breast feeding, or plan to become pregnant during the course of this study.
6. Clinically significant electrocardiogram or laboratory abnormalities at screening that are deemed exclusionary in the opinion of the Principal Investigator.
7. Participants taking any psychotropic medication on a regular basis. Participants will need to be free of all psychotropic medications (one week for psychostimulants, four weeks for all other medications), except for as needed (PRN) benzodiazepines or hypnotics. Allowed psychiatric co-morbidities include social anxiety disorder or dysthymia which does not require treatment.
8. Participants with any concurrent chronic or acute illness or unstable medical condition that could, in the opinion of the study physician, confound the results of safety assessments, increase risk to the participant or lead to difficulty complying with the protocol. Participants who have a history of mental retardation or severe learning disability will be excluded.
9. Participants who in the investigator's opinion meet any of the exclusionary criteria specified on the FDA label of either Droxidopa or carbidopa.
10. Have uncontrolled hypertension, defined as systolic blood pressure >140 millimeters of mercury (mmHg) and/or diastolic blood pressure >110 mmHg or use of ≥2 antihypertensive medications.
11. Known or suspected hypersensitivity to the study medication or any of its ingredients.
12. Have in the investigator's opinion any significant cardiac arrhythmia.
13. Any significant systemic, hepatic, cardiac or renal illness.
14. Diabetes mellitus or insipidus.
15. Have a history of closed angle glaucoma.
16. Have a known or suspected current malignancy. Participants with a history of cancer must be symptom- and treatment-free for at least 5 years prior to randomization, with the exception of participants 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.
17. Participants with known gastrointestinal illness or other gastrointestinal disorder that may, in the investigator's opinion, affect the absorption of study drug.
18. In the investigator's opinion, have clinically significant abnormalities on clinical examination or laboratory testing.
19. In the investigator's opinion, are unable to adequately co-operate because of individual or family situation.
20. Are not able or willing to comply with the study requirements for the duration of the study.
21. Have participated in another clinical trial with an investigational agent (including named participant or compassionate use protocol) within 1 month before the start of the study.
22. 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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Droxidopa+Carbidopa Open-Label; 3 weeks of open label droxidopa (200, 400, or 600 milligrams [mg] three times daily [TID]) monotherapy followed by 3 weeks of droxidopa in combination with carbidopa (25 mg or 50 mg TID).	Drug: Droxidopa+Carbidopa; 3 weeks of open label droxidopa (L-dihydroxyphenylserine (L-DOPS)) (200, 400, or 600mgs TID) monotherapy followed by 3 weeks of droxidopa in combination with carbidopa (25mg or 50mg TID) followed by 2 weeks of double blind continued droxidopa+carbidopa or placebo; Other Names: L-DOPS; L-threo-dihydroxyphenylserine; Droxidopa
Placebo Comparator: Placebo Randomized Period; 2 week double-blind period in which participants either continued to receive droxidopa+carbidopa treatment or placebo	Drug: Droxidopa+Carbidopa; 3 weeks of open label droxidopa (L-dihydroxyphenylserine (L-DOPS)) (200, 400, or 600mgs TID) monotherapy followed by 3 weeks of droxidopa in combination with carbidopa (25mg or 50mg TID) followed by 2 weeks of double blind continued droxidopa+carbidopa or placebo; Other Names: L-DOPS; L-threo-dihydroxyphenylserine; Droxidopa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total AISRS Score at the End of Double-blind Treatment (Week 8)	The AISRS is an 18-item validated investigator-administered instrument for the assessment of ADHD symptoms with an inattentive subscale (9 items) and a hyperactive-impulsive subscale (9 items). The severity of each of the items was rated on a 4-point scale (0-none, 1-mild, 2-moderate, 3-severe). The total score was the sum of the inattentive and hyperactive-impulsive subscales and ranged from 0 (none) to 54 (most severe). A higher score corresponded to a worse severity of ADHD.	Baseline, Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Adult ADHD Self-Report Scale (ASRS) v1.1 Total Score at the End of Double-blind Treatment (Week 8)	ASRS is a validated self-administered, instrument for the assessment of ADHD symptoms. It comprised of 18 items, which were rated by the participant on a 5-point scale (0=never, 1=rarely, 2=sometimes, 3=often, 4=very often). Total ASRS score was the sum of the ordinal response values for the 18 ASRS questions and ranged from 0 (never) to 72 (very often). A higher score corresponded to a worse severity of ADHD.	Baseline, Week 8
Change From Baseline in Global Impairment on the Clinician Global Impression (CGI) Scale at the End of Double-blind Treatment (Week 8)	7-point clinician-rated scale assessing global severity of ADHD ranging from Normal (1), Borderline (2), Mild (3), Moderate (4), Marked (5), Severe (6), to Extremely Severe (7) in functional impairment.	Baseline, Week 8

Collaborators and Investigators

• Sponsor: Chelsea Therapeutics
• Investigators: Principal Investigator: Lenard A Adler, M.D., VA New York Harbor Healthcare System/New York University Langone Medical Center

Publications and helpful links

General Publications

• Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, Faraone SV, Greenhill LL, Howes MJ, Secnik K, Spencer T, Ustun TB, Walters EE, Zaslavsky AM. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006 Apr;163(4):716-23. doi: 10.1176/ajp.2006.163.4.716.
• Adler LA, Gorny SW. Pilot Study of Droxidopa With Carbidopa in Adults With ADHD. J Atten Disord. 2019 Jan;23(2):189-198. doi: 10.1177/1087054715580393. Epub 2015 Apr 23.

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: September 23, 2009
• First Submitted That Met QC Criteria: September 23, 2009
• First Posted (Estimated): September 24, 2009

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: ADHD; Attention Deficit Hyperactivity Disorder; Adult ADHD; Adult Attention Deficit Hyperactivity Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Dyskinesias; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Attention Deficit Disorder with Hyperactivity; Hyperkinesis; 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 ADD201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO