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

Study Overview
=================
Brief Summary
-----------------
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 US adult population, or between 8-9 million individuals (Kessler et al., 2006). 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 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 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 thee times daily. As adult ADHD is characterized as a disorder of decreased NE activity in the pre-frontal cortex, it is hypothesized that treating patients with droxidopa (in co-administration of carbidopa) will have a positive effect on adult ADHD.

Detailed Description
-----------------
This will be a 12-week study of twenty enrolled subjects with DSM IV adult ADHD (age 18-55), with a goal of completing twenty subjects 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-report ADHD symptoms on the ASRS v1.1 Symptom Checklist, global impairment on the Clinician Global Impression Scale (CGI).

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

Conditions
-----------------
Attention Deficit Hyperactivity Disorder

Intervention / Treatment
-----------------
* Drug: Droxidopa+Carbidopa
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: At the time of consent, are between the ages of 18-55, inclusive. Meet DSM-IV criteria for ADHD as assessed by the Adult ADHD Clinician Diagnostic Scale (ACDS) v1.2. 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 SCID. Must have a satisfactory medical assessment with no clinically significant abnormalities as determined by medical history, physical exam, ECG, and clinical laboratory testing. Must be able to swallow capsules. In the opinion of the investigator, the subject must understand and be able, willing and likely to fully comply with the study procedures and restrictions. Must have given signed and dated informed consent in accordance with Good Clinical Practice (GCP) Guidelines. Exclusion Criteria: 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. Uncontrolled comorbid major depressive disorder, anxiety disorder or dysthymia. Women of childbearing potential who are not using a medically accepted contraception. 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. Clinically significant electrocardiogram or laboratory abnormalities at screening that are deemed exclusionary in the opinion of the Principal Investigator. Subjects taking any psychotropic medication on a regular basis. Subjects will need to be free of all psychotropic medications (one week for psychostimulants, four weeks for all other medications), except for PRN benzodiazepines or hypnotics. Allowed psychiatric co-morbidities include social anxiety disorder or dysthymia which does not require treatment. Subjects 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 subject or lead to difficulty complying with the protocol. Subjects who have a history of mental retardation or severe learning disability will be excluded. Subjects who in the investigator's opinion meet any of the exclusionary criteria specified on the FDA label of either Droxidopa or carbidopa. Have uncontrolled hypertension, defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >110 mmHg or use of ≥2 antihypertensive medications. 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. Subjects 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. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Droxidopa+Carbidopa<br>Droxidopa (L-dihydroxyphenylserine (L-DOPS)) (200, 400, or 600mgs TID) in combination with carbidopa (25mg or 50mg TID) | Drug: Droxidopa+Carbidopa<br>* Droxidopa (L-dihydroxyphenylserine (L-DOPS)) (200, 400, or 600mgs TID) in combination with carbidopa (25mg or 50mg TID, provided as oral capsules taken TID from Baseline to end of Week 8<br>* Other names: L-DOPS;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo matched oral capsules taken TID from Baseline to end of Week 8<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome measure will be changes from baseline in total score on the Adult ADHD Investigator Symptom Rating Scale (AISRS). |  | Baseline to end of week 8 treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in self-report ADHD symptoms on the ASRS v1.1 Symptom Checklist |  | baseline to end of 8 Week treatment period | 
| Changes in global impairment on the Clinician Global Impression Scale (CGI). |  | baseline to end of week 8 treatment period | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Attention Deficit Hyperactivity Disorder, ADHD, Adult ADHD, Adult Attention Deficit Hyperactivity Disorder