| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Attention-Deficit/Hyperactivity Disorder (ADHD) |
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| E.1.1.1 | Medical condition in easily understood language |
| A condition making it difficult to control your behavior, activity level and attention level. |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003735 |
| E.1.2 | Term | Attention deficit-hyperactivity disorder |
| E.1.2 | System Organ Class | 100000004873 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of Study LYDO is to test the hypothesis that atomoxetine is superior to placebo in maintaining a satisfactory response at the end of double-blind treatment in adult outpatients with ADHD who show a satisfactory response to acute atomoxetine treatment, as measured by the proportion of patients who meet predefined response criteria.These criteria are specified in an ethical review board (ERB) supplement to the protocol to which the investigator must remain unblinded. |
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| E.2.2 | Secondary objectives of the trial |
Secondary Gatekeeper Objectives:
• To assess the maintenance of efficacy of atomoxetine compared with placebo during double-blind treatment, as measured by the number of days until relapse.
• to assess the quality of life in patients treated with atomoxetine compared with placebo during double-blind treatment, as measured by the mean change from baseline using the AAQoL scores at the last visit of the double-blind period.
Additional Secondary Objectives: Please see protocol
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Sample Banking Addendum B4Z-MC-LYDO(2)
09 January 2008
Eli Lilly and Company (Lilly) has established a program, Combined Specimen Banking (CSB), to bank samples (collectively called Banked Samples) from patients enrolled in studies sponsored by Lilly. The Banked Samples are collected and banked for research to identify the genes and/or gene products and/or biochemical markers associated with diseases and/or response to clinical trial medication or other medication taken during the trial. For example, in Study B4Z-MC-LYDO, the relationship between naturally occurring genetic variants in candidate genes such as the genes for norepinephrine receptors and other genes that may regulate or be regulated by norepinephrine, and response to atomoxetine may be investigated.
Protocol Sample Storage Addendum B4Z-MC-LYDO(3)
09 January 2008
The primary objective is to collect and store blood for research into biomarkers associated with adult ADHD and treatment with atomoxetine.
Assessment will be based on a comparison of the change in plasma levels of NE, DHPG or possibly other analytes in atomoxetine- and placebo-treated patients.
Protocol Addendum B4Z-MC-LYDO(4)
Maintenance of Response After Open-Label Treatment with Atomoxetine Hydrochloride in Adult Outpatients with Attention-Deficit/Hyperactivity Disorder (ADHD): A Placebo-Controlled, Randomized Withdrawal Study
Study Period IV: Open-Label Treatment Extension
The rationale for this addendum is to add an optional open-label treatment extension period (Study Period IV) to Protocol B4Z-MC-LYDO (LYDO) of approximately 2 years for patients living in countries where atomoxetine for the adult Attention-Deficit/Hyperactivity Disorder (ADHD) indication has not been approved by the end of their participation in Study LYDO. Since atomoxetine is not yet approved and/or commercially available in some countries, this optional open-label extension will ensure continuity of care to those patients who may have received a benefit from treatment with atomoxetine and wish to continue in the protocol. |
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| E.3 | Principal inclusion criteria |
[1] Patients must be male or female outpatients who are at least 18 years of age and no more than 50 years of age when informed consent is obtained.
[2] Patients must meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision™ (DSM-IV-TR™) criteria for current ADHD as well as meet criteria for a historical diagnosis of ADHD during childhood as assessed by the Conners’ Adult ADHD Diagnostic Interview for DSM-IV (CAADID). Corroboration for key symptom domains being present during childhood should be obtained through a third-party source of information. A third-party source of information could include, for example, interviewing (by phone or in person) the patient’s spouse, partner, family member, or close friend who can attest that key ADHD symptoms were present during childhood; medical records that establish childhood diagnosis of ADHD; or school records that reference symptoms of key ADHD domains.
[3] Patients must have a score of ≥2 on at least 6 items of either the inattentive or hyperactive core subscales at Visit 1 on the rated CAARS-Inv:SV. In addition, their CAARS-Inv:SV 18-item total ADHD symptom score (the sum of the inattention and hyperactivity/impulsivity subscales) must be ≥20.
[4] Patients must have a score of ≥2 on at least 6 items of either the inattentive or hyperactive core subscales of the CAARS-O:SV for current symptoms (typically as rated by a spouse, partner, parents or other family members, or by a close friend who can provide reliable and trustworthy information). Results need not be obtained in person, provided the observer’s identity and relationship to the patient is documented (the patient can bring the scale to the observer outside of the clinic, or ratings can be obtained by telephone). Observer ratings must be available prior to completing Visit 2.
[5] Patients must have a CGI-ADHD-S score of ≥4 (moderate symptoms) at Visit 1 and Visit 2.
[6] Patients must have laboratory results, including serum chemistries, hematology, and urinalysis, that show no significant abnormalities (significant would include laboratory deviations requiring acute medical intervention or further medical evaluation), and there is no clinical information that, in the judgment of a physician, should preclude a patient’s participation at study entry. A patient with a clinically significant abnormal laboratory result may enter the study if, after appropriate medical evaluation, the result does not indicate a serious medical condition that in the investigator’s judgment would preclude participation. If there is any question about the appropriateness of participation or relevance of a particular finding, the Eli Lilly and Company (Lilly) clinical research physician monitoring the study should be consulted.
[7] Patients must have an electrocardiogram (ECG) performed at Visit 1 or between Visit 1 and Visit 2. The results of the screening ECG must be read, and the results must be available to the investigator or qualified designee, prior to dispensing atomoxetine at Visit 2. If an ECG shows an abnormality, the Algorithm for Assessing Electrocardiogram Abnormalities (Protocol Attachment LYDO.3) for including or excluding the patient should be followed. Patients with other abnormalities may be included at the discretion of the investigator; however, the Lilly physician monitor or designee must be notified. An investigator can choose to exclude any patient from the study on the basis of his/her interpretation of the ECG regardless of another interpretation. (Note: Protocol Attachment LYDO.4 summarizes the adult ECG exclusion criteria.)
[8] Patients must have been judged by the investigator to be reliable to keep appointments for clinic visits and all tests, including venipuncture and examinations, required by the protocol.
[9] Patients must possess an educational level and degree of understanding of the language of their country that enables them to communicate suitably with the investigator and study coordinator.
[10] (Note: This inclusion criterion applies only to females of childbearing potential—those women not surgically sterilized and between menarche and 1 year postmenopause). Women must test negative for pregnancy at the time of enrollment based on a serum pregnancy test and, if sexually active, agree to use a reliable method of birth control (for example, but not limited to, use of oral contraceptives or contraceptive implants; a reliable barrier method of birth control [diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam]; intrauterine devices; or partner with vasectomy) during the study.
[11] Patients must be able to swallow capsules.
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| E.4 | Principal exclusion criteria |
[12] Patients who meet full DSM-IV-TR diagnostic criteria for any history of bipolar disorder, current major depression, a current anxiety disorder (including generalized anxiety disorder, panic disorder, or social phobia), or any history of a psychotic disorder (confirmed by the structured interview). Assessment will be by clinical history and a Structured Clinical Interview for DSM-IV Axis I disorders (SCID). If the investigator believes that such a diagnosis has previously been made in error, he/she should contact the sponsor and discuss the case history with the Lilly physician responsible for the study prior to allowing the patient to enter the study.
[13] Patients with clinically significant depression or anxiety, as measured by HAMD 17 or HAMA scores ≥15 at Visit 2.
[14] Patients with organic brain disease; for example, dementia, traumatic brain injury residual, or a history of any seizure disorder (except febrile seizures during childhood). In addition, patients taking anticonvulsants for seizure control currently or at any time in the past.
[15] Patients with hyperthyroidism or hypothyroidism. Patients who were previously diagnosed with hyperthyroidism or hypothyroidism who are clinically and chemically euthyroid and whose dose of thyroid supplement has been stable for at least the past 3 months (and who are expected to be euthyroid for the trial duration) are allowed to participate in the study. In some cases, investigators may require regular thyroid followup, as clinically indicated.
[16] Patients who, in the opinion of the investigator, are at serious suicidal or homicidal risk.
[17] Patients with a history of allergy to atomoxetine, severe allergies to more than 1 class of medications, or multiple adverse drug reactions.
[18] Patients who have a known history of glaucoma.
[19] Male patients with a history of difficulty starting a stream of urine or other symptoms suggestive of prostate enlargement, or other evidence of urinary hesitancy on clinical history.
[20] Female patients who are pregnant or nursing.
[21]Patients taking psychotropic medications, including health food supplements judged by the investigator to be likely to have central nervous system activity (for example, St John’s Wort, gingko leaf, melatonin). If the patient is taking the medication prior to study entry, there must be a washout period equal to a minimum of 5 half-lives of that medication prior to Visit 2. If the half-life of a medication is unknown (for example, herbal products), then the patient should have a 28-day medication washout.
[22] Patients who are currently using alcohol, drugs of abuse, or any prescribed or over-the-counter medication in a manner which the investigator considers indicative of chronic abuse or who meet DSM IV-TR criteria for alcohol or other substance dependence.
[23] Patients with significant medical conditions that are likely to become unstable during the trial or would likely be destabilized by treatment with atomoxetine (for example, cardiovascular disease that would be aggravated by increased pulse or blood pressure), or require treatment with excluded medications.
[24] Patients who have any medical condition (for example, catecholamine-secreting neural tumor) that has sympathomimetic activity, or who are taking a medication on a daily basis (for example, albuterol, inhalation aerosols, pseudoephedrine) that has sympathomimetic activity.
[25] Patients who have used monoamine oxidase inhibitors (MAOIs) within 2 weeks (14 days) of Visit 2.
[26] Patients who have a current or past history of hypertension. For the purposes of this protocol, hypertension will be defined as average systolic or diastolic blood pressure, measured on at least 2 separate occasions prior to Visit 1, 140/90. Patients whose blood pressure is controlled with nonexcluded medication are eligible for inclusion.
[27] Patients who are at any time likely to begin structured psychotherapy aimed at ADHD symptoms during the study or to change the intensity of psychotherapy during the study. Psychotherapy initiated at least 1 month prior to Visit 1 is acceptable.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy measure is the proportion of patients maintaining a response at the end (Visit 18) of the double-blind treatment phase. Any patient who discontinues during the double-blind post-randomization period will be treated as a non-responder for this analysis. More detail of the definition of response will be described in the statistical analysis plan and the ERB supplement. The treatment comparison of proportions will be tested using Fisher’s exact test.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Following primary endpoint study completion at V18. |
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| E.5.2 | Secondary end point(s) |
To assess the maintenance of efficacy as measured by the number of days until relapse
To assess the quality of life as measured by AAQoL scores
Assess maintenance of ATX efficacy
Assess executive function as measured by the BRIEF-A:Self Report and BRIEF-A:Informant
Assess quality of life as measured by the EQ-5D
Assess consistency of efficacy among geographic regions
Add'l validation information on AAQoL
Assess safety. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Following primary endpoint study completion at V18. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| There is an optional open label extension (Protocol Addendum B4Z-MC-LYDO(4)) |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Austria |
| Belgium |
| Canada |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Mexico |
| Netherlands |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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