E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029227 |
E.1.2 | Term | Neuralgia trigeminal |
E.1.2 | System Organ Class | 100000004852 |
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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 |
To investigate the effect of repeat oral dosing of CNV1014802 on the pain experienced in trigeminal neuralgia |
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E.2.2 | Secondary objectives of the trial |
• To investigate the safety and tolerability of CNV1014802 in patients with trigeminal neuralgia • To assess the plasma concentrations and exposures of CNV1014802 • To assess the use of the Brief Pain Inventory – Facial as an assessment measure for quality of life in trigeminal neuralgia • To explore the frequency of genetic mutation in sodium and calcium channels in TGN and the relationship to response to CNV1014802 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A patient will be eligible for inclusion in this study only if all of the following criteria apply: 1. IHS criteria for trigeminal neuralgia to be used. The diagnosis must be verified by a member of the diagnostic sub-committee of the DMC before the patient is entered into the study. A diagnosis of trigeminal neuralgia. Pain must be unilateral, and characterized by brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve. Pain is commonly evoked by trivial stimuli including washing, shaving, smoking, talking and/or brushing the teeth(trigger factors), and frequently occurs spontaneously. The attacks start and end rapidly. There is often no pain between each bout of pain and many bouts can occur every day. There is often a refractory period between attacks. Some patients may report some after pain after the severe pain for a few minutes. Pain remissions occur where there can be weeks or months of no pain even when medications are stopped. The following diagnostic criteria for trigeminal neuralgia must be met: a. Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, affecting one or more divisions of the trigeminal nerve and fulfilling criteria b and c. b. Pain has at least one of the following characteristics: i. Intense, sharp, superficial or stabbing ii. Precipitated from trigger areas or by trigger factors c. Attacks are stereotyped in the individual patient d. There is no clinically evident neurological deficit e. Not attributed to another disorder 2. Frequency criteria for numbers of paroxysms: • Patients must have suffered a minimum of 3 or more paroxysms of pain per day, rated at an intensity of 4 or more on the pain NRS, on at least 4 days during the last 7 days prior to entry into the open-label treatment period. 3. Male or female between 18 and 80 years of age inclusive, at the time of signing the informed consent. 4. A female patient is eligible to participate if she is of: • Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) ≥ 25.8 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 7.5 if they wish to continue their HRT during the study. • Child-bearing potential and agrees to use one of the contraception methods listed in Section 7.5 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female patients must agree to use contraception until 3 days post-last dose. 5. Male patients must agree to use one of the contraception methods listed in Section 7.5. This criterion must be followed from the time of the first dose of study medication until 14 days post-last dose. 6. Body weight ≥ 50 kg for men and ≥ 45 kg for women. 7. BMI ≤34.9. 8. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Informed consent must be obtained prior to the commencement of any study related procedures. 9. Three ECGs taken at least 5 min apart should be performed at Screening. QTcF < 450 msec in at least two of the three ECGs . 10. AST and ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 11. Approved concomitant medications must have been stable for at least 3 weeks prior to day 0.
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E.4 | Principal exclusion criteria |
• Patients who are known non-responders to sodium channel blockers at therapeutic doses. • Patients with causes for their facial pain other than that specified in Inclusion Criterion • A positive pre-study drug screen. • A positive history of HIV. • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. • History of any liver disease within the last 6 months, with the exception of known Gilbert’s disease. • History of excessive regular alcohol consumption within 6 months of the study. • Patients with a history or risk of seizures or a history of epilepsy, head injury or related neurological disorders • Patients with a history of uncontrolled or poorly controlled hypertension, with systolic BP frequently exceeding 160mmHg and/or diastolic BP frequently exceeding 100mmHg, or patients who have BP greater than or equal to 160mmHg systolic and/or greater than or equal to 100mmHg diastolic at screening after repeated measurements • History or presence of significant cardiovascular, gastrointestinal, or renal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs. • Patients with conditions known to affect cardiac conduction or a personal or familial history of Brugada syndrome • Pregnant females or lactating females. • History or presence of any clinically significant abnormality in vital signs / ECG / laboratory tests or have any medical or psychiatric condition, which, in the opinion of the Investigator may interfere with the study procedures or compromise patient safety. • History of suicidal ideation and/or suicide attempts or clinical evidence of recent major depression. • Patients who are unable to maintain approved medications for their trigeminal neuralgia at a stable dose during the study. • Unable to refrain from excessive use of sedatives. • Unable to comply with the prohibited concomitant medication restrictions as detailed in the protocol. This includes but is not limited to sodium channel blockers or drugs that adversely interact with a monoamine oxidase- B inhibitor: MAOI’s, antidepressants, opioids and sympathomimetic agents. • History of hypersensitivity to CNV1014802. • The patient has participated in a clinical trial and has received an investigational product within 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) prior to the start of this study. • Exposure to more than four new chemical entities (medications for which no marketing authorization has been obtained) within 12 months prior to the first dosing day. • Where participation in the study would result in total donation of blood or blood products in excess of 500mL within a 56 day period. • Patient is mentally or legally incapacitated. • Unwillingness or inability to follow the procedures outlined in the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Patients will be classified as a treatment failure if they meet one of the following criteria:
• 50% increase in the frequency of paroxysms compared to the final 7 days of the open-label period, to more than 3 paroxysms within a 7 day period • When more than 3 paroxysms are reported in a 7 day period, 50% increase in the severity of pain experienced in the paroxysms compared to the final 7 days of the open-label period • A Patient Global Improvement of Change rating of much worse/very much worse • The patient discontinues the study due to ‘Lack of Efficacy’ • The patient discontinues due to an adverse reaction or poor tolerability considered to be related to study medication |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The frequency and the severity of paroxysms will be recorded on a daily basis by the patient. The patient and clinician global impression of change rating will be determined on Day 21 and Day 49. |
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E.5.2 | Secondary end point(s) |
Efficacy Endpoints: • Number and severity of paroxysms of pain in the 21 day open-label period both evoked and spontaneous. • Average 24 hour pain intensity numerical rating scale (PI-NRS) • Patient and Physician Clinical Global Impression of Change • Brief Pain Inventory – Facial Pharmacokinetics: • Pre-dose and post-dose plasma CNV1014802 concentrations – AUC-ss, Ctrough-ss and Cmax-ss
Safety: • Adverse events • Vital signs • ECG parameters • Laboratory safety tests (clinical chemistry, haematology, urinalysis)
Exploratory Endpoints: • Assessing PK-PD relationship, if data permit. • Cognitive function using the Medical Outcome Study - Cognitive Scale • Adverse event profile (AEP) scale • Presence of genetic mutations in sodium channel (Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7) or calcium channel (Cav2.2 and Cav2.1) genes (optional for patients). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The frequency and the severity of paroxysms will be recorded on a daily basis by the patient. The patient and clinician global impression of change rating will be determined on Day 21 and Day 49. The brief pain inventory - facial will be determined on Day 0, 21, 49 and 56. Pharmacokinetics will be assessed on Day 0, 7, 21, 35 and 49. Vital signs and ECGs will be assessed in screening and on Day 0, 7, 14, 21, 28, 35, 42, 49 and 56.Lab safety samples will be taken in screening and on Day 0, 7, 21, 35, 49 and 56. Cognitive status will be assessed on Day 0, 21 and 49. Adverse event profile scale will be determined in screening and on Day 21 and 49. Adverse events will be collected throughout. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 |
Randomised withdrawal design |
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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.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 1 |
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 | 1 |