Clinical trial NCT00334880: Study to Assess the Safety and Efficacy of NRP104 in Adults With Attention-Deficit Hyperactivity Disorder (ADHD)
Official title: A Phase III, Randomized, Double-Blind, Multi-Center, Placebo-Controlled, Parallel-Group, Forced Dose Titration, Safety and Efficacy Study of NRP104 in Adults With Attention-Deficit Hyperactivity Disorder (ADHD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Attention Deficit Hyperactivity Disorder
Attention Deficit Disorders With Hyperactivity
Attention Deficit Hyperactivity Disorders
Keywords: Attention Deficit Hyperactivity Disorder
Attention Deficit Disorders with Hyperactivity
Attention Deficit Hyperactivity Disorders
Lead sponsor: New River Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2006-06-08
Enrollment: 420
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and effectiveness of NRP104 administered as a daily morning dose (30, 50, and 70mg/day) compared to placebo in adults (18-55 years of age inclusive) diagnosed with moderate to severe Attention Deficit Hyperactivity Disorder (ADHD).

Detailed description: This study is a randomized, phase III, multi-center, placebo-controlled, parallel-group, forced dose titration in which adult subjects (18-55 years of age inclusive) with ADHD will be randomized to NRP104 (30, 50, or 70 mg) or placebo for four weeks of double-blind evaluation of safety and efficacy.

The study will have three phases: (1) screening and washout; (2) baseline; and (3) 4-week double-blind evaluation of NRP104 and placebo. The double-blind period will include a forced dose titration phase followed by a fixed dose phase. Subjects will be required to visit the site up to 6 times over a 5-8 week period, or longer in cases requiring a 28-day wash out.

Screening and Washout: Subjects will be screened to establish eligibility for study participation. The Screening Visit (Visit 1) may take place over multiple days if needed to accommodate the subject's schedule. Those subjects who meet eligibility requirements will undergo medication washout, if applicable. The length of the ADHD medication washout period will range from 7-28 days.

Baseline: Following medication washout, subjects will return to the clinic for reassessment of eligibility criteria and establishment of baseline measures. The interval between the first day of the Screening Visit (informed consent date) and the Baseline Visit (Visit 2) must not exceed 35 days. Eligible subjects with a baseline ADHD-RS score greater than or equal to 28 (performed using adult DSM-IV prompts) will be randomized to treatment.

Double-blind treatment: Eligible subjects will be randomly assigned (in a 2:2:2:1 ratio of each of the three active doses vs. placebo) to a daily morning dose of NRP104 or placebo for 4 weeks. All NRP104 groups will start at a dose of 30 mg/day. Subjects randomized to 70 mg will be titrated to that dose over a 2-week period; those randomized to 50 mg will be titrated to that dose over a 1-week period; and those randomized to 30 mg will begin dosing on 30 mg per day during week one and will remain on that dose throughout the study. Double-blind assessment of the safety and efficacy of NRP104 will proceed for 4 weeks with weekly clinic visits scheduled for evaluations and medication disbursement.

Follow-up period: Subjects who have completed at least 2 weeks of double-blind participation, will have the option to continue participation in an open-label extension study (Protocol NRP104.304: one-year safety study). Subjects who are not eligible or who choose not to participate in the extension study will continue to be followed for thirty days following their last dose of study drug. A telephone contact (or contact in person) will be initiated by the research site to collect any new or ongoing SAEs and to follow-up on any unresolved or related AEs from the Final Study Visit or Early Termination (ET) Visit (Visit 6). If the Principal Investigator determines AEs are not acceptably resolved, appropriate follow-up should continue until all safety concerns, in the opinion of the Investigator, are resolved.

Eligibility criteria: Inclusion Criteria:

* Must be 18-55 years of age, inclusive.
* Must be male or non-pregnant female. Females of childbearing potential (FOCP) must use contraception.
* Must have a medical assessment with no clinically significant or relevant abnormalities as determined by medical history, PE, clinical and lab evaluation.
* Must have 12-lead ECGs defined by the following parameters:

  1. QT/QTcF interval \< 450 msec for males and \< 470 msec for females
  2. Resting heart rate is between 40 and 100 beats per minute
  3. P-R interval \< 200 msec
  4. QRS interval \<110 msec.
* Meets Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; Text Revision (DSM-IV-TR™) criteria for a primary diagnosis of ADHD (diagnostic code 314.00 and 314.01) established by a psychiatric evaluation that reviews DSM-IV-TR™ criteria with at least 6 of the 9 subtype criteria met. The Adult ADHD Clinical Diagnostic Scale (ACDS v1.2) will be utilized as the diagnostic tool.
* Has a baseline ADHD-RS score greater than or equal to 28 assessed using adult DSM-IV prompts.
* Understands and is able, willing, and likely to fully comply with the study procedures and restrictions.
* Has given written informed consent to participate in the study in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines and applicable regulations before completing any study procedures.

Exclusion Criteria:

* In the opinion of the investigator, the subject is significantly underweight \[e.g., Body Mass Index (BMI) \< 18.5\] or morbidly obese.
* Has any comorbid psychiatric diagnosis with significant symptoms such as any severe comorbid Axis II disorders or severe Axis I disorders including Post Traumatic Stress Disorder (PTSD), psychosis, bipolar illness, severe obsessive compulsive disorder, severe depressive or severe anxiety disorder or other symptomatic manifestations that will contraindicate NRP104 treatment or confound efficacy or safety assessments. Specifically, subjects with mild to moderate forms of Axis I disorders including social phobia and dysthymia may be included while subjects with a lifetime history of psychosis or bipolar disorder will be excluded from participation. Comorbid psychiatric diagnoses will be established by a psychiatric evaluation that includes the Structured Clinical Interview for DSM-IV-TR™ disorders (SCID-I) interview at the screening visit.
* Has any concurrent chronic or acute illness or unstable medical condition that could confound the results of safety assessments, increase risk to the subject or lead to difficulty complying with the protocol. Subjects with mental retardation or a severe learning disability are excluded.
* Has a history of seizure (other than infantile febrile seizures), any tic disorder, or a current diagnosis and/or family history of Tourette's Disorder.
* Has a known cardiac structural abnormality or any other condition that may affect cardiac performance.
* Has any clinically significant ECG or laboratory abnormality at Screening or Baseline.
* Subject has a history of hypertension or has a resting sitting systolic blood pressure \> 139mmHg or diastolic blood pressure \> 89mmHg.
* Has used any prohibited medication except for ADHD medications within 30 days of screening visit. Hormonal contraceptives are acceptable.
* Has a documented allergy, intolerance, or documented history of non-responsivity to methylphenidate or amphetamine.
* Currently has (or had a history within the last 6 months of) a drug dependence or substance abuse disorder according to DSM-IV-TR™ criteria (excluding nicotine) as established by a SCID-I at the screening visit.
* Has a positive urine drug result at Screening (with the exception of subject's current stimulant therapy, if any) or at Baseline.
* Has taken an investigational drug or taken part in a clinical trial within 30 days prior to Screening.
* The female subject is pregnant or lactating.

Primary outcomes:
measure: Clinician-administered ADHD-rating scale (ADHD-RS) performed using adult DSM-IV prompts
timeFrame: weekly over a period of 4 weeks
Secondary outcomes:
measure: The Clinical Global Impression of Improvement (CGI-I)
timeFrame: 4 times over a period of 4 weeks
measure: Self-report of the Pittsburgh Sleep Quality Index (PSQI) measured at Baseline and at the Final Study Visit
timeFrame: twice over a period of 4 weeks
measure: Occurrence of treatment-emergent adverse events and specific evaluation of blood pressure, heart rate, electrocardiogram (ECG), laboratory findings, and physical examination (PE)
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Clinical Study Centers, LLC
state: Arkansas
city: El Centro
country: United States
facility: Valley Clinical Research, Inc.
state: California
city: Irvine
country: United States
facility: University of California, Irvine Child Development Center
state: California
city: LaFayette
country: United States
facility: Bay Area Research Institute
state: California
city: Rolling Hills Estate
country: United States
facility: Peninsula Research Associates
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco, Dept. of Psychiatry
state: California
city: Spring Valley
country: United States
facility: Encompass Clinical Research
state: California
city: Boulder
country: United States
facility: Alpine Clinical Research Center
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: New London
country: United States
facility: Psychiatric Medicine Center
state: Connecticut
city: Fort Myers
country: United States
facility: Gulfcoast Clinical Research Center
state: Florida
city: Miami
country: United States
facility: Miami Research Associates
state: Florida
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions, Inc.
state: Florida
city: Tampa
country: United States
facility: Meridien Research
state: Florida
city: West Palm Beach
country: United States
facility: Janus Center for Psychiatric Research LLC
state: Florida
city: Roswell
country: United States
facility: Northwest Behavioral Research Center
state: Georgia
city: Smyrna
country: United States
facility: Carman Research
state: Georgia
city: Overland Park
country: United States
facility: Psychiatric Associates
state: Kansas
city: Overland Park
country: United States
facility: Vince and Associates Clinical Research
state: Kansas
city: Lutherville
country: United States
facility: Johns Hopkins at Green Spring Station
state: Maryland
city: Rockville
country: United States
facility: Marc Hertzman, MD
state: Maryland
city: Cambridge
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Flint
country: United States
facility: Summit Research Network (Michigan) Inc.
state: Michigan
city: Rochester Hills
country: United States
facility: Rochester Center for Behavioral Medicine
state: Michigan
city: St Charles
country: United States
facility: St Charles Psychiatric Associates-Midwest Research
state: Missouri
city: St. Louis
country: United States
facility: Mercy Health Research
state: Missouri
city: Las Vegas
country: United States
facility: Center for Psychiatry and Behavioral Medicine
state: Nevada
city: Clementon
country: United States
facility: CNS Research Institute (CRI)
state: New Jersey
city: New York
country: United States
facility: VA NY Harbor Healthcare System
state: New York
city: Durham
country: United States
facility: Duke University ADHD Program
state: North Carolina
city: Raleigh
country: United States
facility: Richard Weisler and Associates
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals of Cleveland, Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: IPS Research Company
state: Oklahoma
city: Portland
country: United States
facility: Oregon Center for Clinical Investigations, Inc.
state: Oregon
city: Philadelphia
country: United States
facility: CNS Research Institute, P.C.
state: Pennsylvania
city: Austin
country: United States
facility: FutureSearch Trials
state: Texas
city: Bellaire
country: United States
facility: Claghorn-Lesem Research Clinic
state: Texas
city: Houston
country: United States
facility: Bayou City Research
state: Texas
city: Houston
country: United States
facility: Red Oak Psychiatry Associates, P.A.
state: Texas
city: Lake Jackson
country: United States
facility: R/D Clinical Research, Inc.
state: Texas
city: Lubbock
country: United States
facility: John M. Turnbow, MD, PA
state: Texas
city: Burlington
country: United States
facility: The Clinical Study Center
state: Vermont
city: Woodstock
country: United States
facility: Neuropsychiatric Associates
state: Vermont
city: Charlottesville
country: United States
facility: Psychiatric Alliance of the Blue Ridge Clinical Research
state: Virginia
city: Herndon
country: United States
facility: NeuroScience, Inc.
state: Virginia
city: Virginia Beach
country: United States
facility: Brighton Research Group
state: Virginia
city: Seattle
country: United States
facility: Summit Research Network LLC (Seattle)
state: Washington
Study officials:
affiliation: Massachusetts General Hospital
name: Joseph Biederman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Adler LA, Goodman DW, Kollins SH, Weisler RH, Krishnan S, Zhang Y, Biederman J; 303 Study Group. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008 Sep;69(9):1364-73. doi: 10.4088/jcp.v69n0903. Epub 2008 Sep 9.
citation: Mattingly GW, Weisler RH, Young J, Adeyi B, Dirks B, Babcock T, Lasser R, Scheckner B, Goodman DW. Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. BMC Psychiatry. 2013 Jan 29;13:39. doi: 10.1186/1471-244X-13-39.
citation: Babcock T, Dirks B, Adeyi B, Scheckner B. Efficacy of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder previously treated with amphetamines: analyses from a randomized, double-blind, multicenter, placebo-controlled titration study. BMC Pharmacol Toxicol. 2012 Dec 19;13:18. doi: 10.1186/2050-6511-13-18.
citation: Surman CB, Roth T. Impact of stimulant pharmacotherapy on sleep quality: post hoc analyses of 2 large, double-blind, randomized, placebo-controlled trials. J Clin Psychiatry. 2011 Jul;72(7):903-8. doi: 10.4088/JCP.11m06838.
citation: Waxmonsky JG, Waschbusch DA, Glatt SJ, Faraone SV. Prediction of placebo response in 2 clinical trials of lisdexamfetamine dimesylate for the treatment of ADHD. J Clin Psychiatry. 2011 Oct;72(10):1366-75. doi: 10.4088/JCP.10m05979pur.
citation: Adler LA, Weisler RH, Goodman DW, Hamdani M, Niebler GE. Short-term effects of lisdexamfetamine dimesylate on cardiovascular parameters in a 4-week clinical trial in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2009 Dec;70(12):1652-61. doi: 10.4088/JCP.09m05335pur.
citation: Adler LA, Goodman D, Weisler R, Hamdani M, Roth T. Effect of lisdexamfetamine dimesylate on sleep in adults with attention-deficit/hyperactivity disorder. Behav Brain Funct. 2009 Aug 3;5:34. doi: 10.1186/1744-9081-5-34.